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Ekeuku, Sophia Ogechi, Nuraqila Mohd Murshid, Siti Nursyazwani Shukri, Nur Fatin Nabilah Mohd Sahardi, and Suzana Makpol. "Effect of Vitamin E on Transcriptomic Alterations in Alzheimer’s Disease." International Journal of Molecular Sciences 24, no. 15 (August 3, 2023): 12372. http://dx.doi.org/10.3390/ijms241512372.
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Research into ageing is focused on understanding why some people can maintain cognitive ability and others lose autonomy, affecting their quality of life. Studies have revealed that age-related neurodegenerative disorders like Alzheimer’s disease (AD) are now major causes of death among the elderly, surpassing malignancy. This review examines the effects of vitamin E on transcriptomic changes in ageing and neurodegenerative diseases, using AD as an example, and how different transcriptome profiling techniques can shape the results. Despite mixed results from transcriptomic studies on AD patients’ brains, we think advanced technologies could offer a more detailed and accurate tool for such analysis. Research has also demonstrated the role of antioxidant modifiers in preventing AD. This review will explore the key findings regarding AD and its modulation by vitamin E, emphasizing the shift in its epidemiology during the ageing process.
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Marano, Domenico, Salvatore Fioriniello, Maurizio D’Esposito, and Floriana Della Ragione. "Transcriptomic and Epigenomic Landscape in Rett Syndrome." Biomolecules 11, no. 7 (June 30, 2021): 967. http://dx.doi.org/10.3390/biom11070967.
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Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein 2 (MECP2) gene, which encodes a multifunctional reader of methylated DNA. MeCP2 is a master epigenetic modulator of gene expression, with a role in the organization of global chromatin architecture. Based on its interaction with multiple molecular partners and the diverse epigenetic scenario, MeCP2 triggers several downstream mechanisms, also influencing the epigenetic context, and thus leading to transcriptional activation or repression. In this frame, it is conceivable that defects in such a multifaceted factor as MeCP2 lead to large-scale alterations of the epigenome, ranging from an unbalanced deposition of epigenetic modifications to a transcriptional alteration of both protein-coding and non-coding genes, with critical consequences on multiple downstream biological processes. In this review, we provide an overview of the current knowledge concerning the transcriptomic and epigenomic alterations found in RTT patients and animal models.
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Ahn, Antonio, Euan J. Rodger, Jyoti Motwani, Gregory Gimenez, Peter A. Stockwell, Matthew Parry, Peter Hersey, Aniruddha Chatterjee, and Michael R. Eccles. "Transcriptional Reprogramming and Constitutive PD-L1 Expression in Melanoma Are Associated with Dedifferentiation and Activation of Interferon and Tumour Necrosis Factor Signalling Pathways." Cancers 13, no. 17 (August 24, 2021): 4250. http://dx.doi.org/10.3390/cancers13174250.
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Melanoma is the most aggressive type of skin cancer, with increasing incidence worldwide. Advances in targeted therapy and immunotherapy have improved the survival of melanoma patients experiencing recurrent disease, but unfortunately treatment resistance frequently reduces patient survival. Resistance to targeted therapy is associated with transcriptomic changes and has also been shown to be accompanied by increased expression of programmed death ligand 1 (PD-L1), a potent inhibitor of immune response. Intrinsic upregulation of PD-L1 is associated with genome-wide DNA hypomethylation and widespread alterations in gene expression in melanoma cell lines. However, an in-depth analysis of the transcriptomic landscape of melanoma cells with intrinsically upregulated PD-L1 expression is lacking. To determine the transcriptomic landscape of intrinsically upregulated PD-L1 expression in melanoma, we investigated transcriptomes in melanomas with constitutive versus inducible PD-L1 expression (referred to as PD-L1CON and PD-L1IND). RNA-Seq analysis was performed on seven PD-L1CON melanoma cell lines and ten melanoma cell lines with low inducible PD-L1IND expression. We observed that PD-L1CON melanoma cells had a reprogrammed transcriptome with a characteristic pattern of dedifferentiated gene expression, together with active interferon (IFN) and tumour necrosis factor (TNF) signalling pathways. Furthermore, we identified key transcription factors that were also differentially expressed in PD-L1CON versus PD-L1IND melanoma cell lines. Overall, our studies describe transcriptomic reprogramming of melanomas with PD-L1CON expression.
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Mattei, Daniele, Andranik Ivanov, Marc van Oostrum, Stanislav Pantelyushin, Juliet Richetto, Flavia Mueller, Michal Beffinger, et al. "Enzymatic Dissociation Induces Transcriptional and Proteotype Bias in Brain Cell Populations." International Journal of Molecular Sciences 21, no. 21 (October 26, 2020): 7944. http://dx.doi.org/10.3390/ijms21217944.
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Different cell isolation techniques exist for transcriptomic and proteotype profiling of brain cells. Here, we provide a systematic investigation of the influence of different cell isolation protocols on transcriptional and proteotype profiles in mouse brain tissue by taking into account single-cell transcriptomics of brain cells, proteotypes of microglia and astrocytes, and flow cytometric analysis of microglia. We show that standard enzymatic digestion of brain tissue at 37 °C induces profound and consistent alterations in the transcriptome and proteotype of neuronal and glial cells, as compared to an optimized mechanical dissociation protocol at 4 °C. These findings emphasize the risk of introducing technical biases and biological artifacts when implementing enzymatic digestion-based isolation methods for brain cell analyses.
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Dufva, Olli, Petri Pölönen, Oscar Brück, Mikko A. Keränen, Juha Mehtonen, Sanna M. Siitonen, Suvi-Katri Leivonen, et al. "Immunogenomic Landscape of Hematological Malignancies." Blood 132, Supplement 1 (November 29, 2018): 2596. http://dx.doi.org/10.1182/blood-2018-99-118335.
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Abstract Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. How cancer-cell intrinsic genomic and epigenetic alterations influence immune signatures in hematological malignancies is not known. Here, we integrated over 8,000 transcriptomes of hematologic cancers and multilevel genomic datasets to investigate associations of immune states to cancer molecular subtypes, genetic and epigenetic alterations, and clinical outcomes. We utilized a resource of over 8,000 transcriptomes collected across 36 hematologic malignancies and normal hematopoietic cells (Hemap), together with multi-omics datasets of acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) from The Cancer Genome Atlas and other sources (Figure). In addition to gene expression data, we integrated somatic DNA alterations, methylation data, multiplex immunohistochemistry (mIHC), and flow cytometry to comprehensively map immune-associated features and validate the robustness of the findings. To characterize the composition of the cytolytic immune infiltrate from bulk transcriptomes, we defined a signature of genes most specifically expressed in cytotoxic CD8+ T lymphocytes and natural killer (NK) cells termed cytolytic score. We found significant heterogeneity in the cytotoxic lymphocyte infiltration signature across hematologic malignancies. Highest cytolytic infiltrate was detected in lymphomas and correlated with IFN-γ and myeloid cell infiltration signatures including CXCL9-11 and IDO1, distinguishing the lymphoma microenvironment from leukemias. In addition to transcriptomic microenvironmental properties, specific genetic alterations were associated with cytotoxic lymphocyte infiltration. In DLBCL, driver alterations enriched in the germinal center B-cell like (GCB) molecular subtype including BCL2 translocations and KMT2D were linked to an immune-cold transcriptomic phenotype. In contrast, DTX1 alterations defined immune-infiltrated lymphomas within the GCB molecular subtype. In AML, TP53 mutations and complex karyotype were enriched in a distinct tSNE-based transcriptomic cluster characterized by increased immune infiltration in the bone marrow (BM). Given the importance of effective antigen presentation for adaptive anti-tumor immune responses, we aimed to understand the transcriptional regulation of HLA genes and co-stimulatory and co-inhibitory signaling in subtypes of hematological malignancies. Downregulation of the antigen-presenting HLA II genes was associated with CpG methylation of the promoter region of the HLA class II master regulator CIITA in distinct transcriptomic clusters of AML harboring PML-RARA or NPM1 alterations. Expression of genes encoding immune checkpoint molecules was strongly influenced by the cell-of-origin and microenvironment of each cancer type. We identified novel associations of inhibitory immune checkpoint molecules to disease subtypes, such as VISTA/PD1-H enriched in myeloid malignancies including AML, CML, and MDS, validated by mIHC performed on BM biopsies. Furthermore, variation in the expression of several genes encoding immune checkpoints was associated with somatic mutations (e.g. CD70 in DLBCL), copy-number alterations (e.g. MICB in DLBCL), and DNA methylation (e.g. PDL1 and PDCD1LG2 in AML). Finally, we integrated GTEx gene expression data across tissues to define cancer-germline antigens (CGAs) with an immune privileged tissue expression pattern. CGAs were frequently expressed in multiple myeloma and DLBCL compared to other hematologic malignancies. CGA expression was associated with cytogenetic alterations and increased MYC activity signature in myeloma and CD58 and KLHL6 mutations in DLBCL. In addition, CGA expression in myeloma and DLBCL was linked to reduced antigen gene promoter methylation and decreased survival. In summary, our findings demonstrate that molecular subtypes of hematological malignancies harbor distinct immunological signatures influenced by genetic and epigenetic alterations. Integrating genetic, epigenetic, and transcriptomic data may facilitate the development of precision immune intervention strategies in hematological malignancies. Figure. Figure. Disclosures Leppa: Bayer: Research Funding; Celgene: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Honoraria, Research Funding.
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Abida, Wassim, Joanna Cyrta, Glenn Heller, Davide Prandi, Joshua Armenia, Ilsa Coleman, Marcin Cieslik, et al. "Genomic correlates of clinical outcome in advanced prostate cancer." Proceedings of the National Academy of Sciences 116, no. 23 (May 6, 2019): 11428–36. http://dx.doi.org/10.1073/pnas.1902651116.
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Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
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Sindona, Cinzia, Michele Runci Anastasi, Luigi Chiricosta, Agnese Gugliandolo, Serena Silvestro, Placido Bramanti, Piero Cascone, and Emanuela Mazzon. "Temporomandibular Disorders Slow Down the Regeneration Process of Masticatory Muscles: Transcriptomic Analysis." Medicina 57, no. 4 (April 7, 2021): 354. http://dx.doi.org/10.3390/medicina57040354.
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Background and Objectives: Musculoskeletal injuries represent a pathological condition due to limited joint motility and morphological and functional alterations of the muscles. Temporomandibular disorders (TMDs) are pathological conditions due to alterations in the musculoskeletal system. TMDs mainly cause temporomandibular joint and masticatory muscle dysfunctions following trauma, along with various pathologies and inflammatory processes. TMD affects approximately 15% of the population and causes malocclusion problems and common symptoms such as myofascial pain and migraine. The aim of this work was to provide a transcriptomic profile of masticatory muscles obtained from TMD migraine patients compared to control. Materials and Methods: We used Next Generation Sequencing (NGS) technology to evaluate transcriptomes in masseter and temporalis muscle samples. Results: The transcriptomic analysis showed a prevalent downregulation of the genes involved in the myogenesis process. Conclusions: In conclusion, our findings suggest that the muscle regeneration process in TMD migraine patients may be slowed, therefore therapeutic interventions are needed to restore temporomandibular joint function and promote healing processes.
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Aschauer, Lydia, Leonhard N. Gruber, Alice Limonciel, Martin O. Leonhard, Walter Pfaller, Anja Wilmes, and Paul Jennings. "Transcriptomic and functional alterations during renal epithelial maturation." Toxicology Letters 211 (June 2012): S161. http://dx.doi.org/10.1016/j.toxlet.2012.03.584.
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Goldenberg, Regina Coeli dos Santos, Dumitru A. Iacobas, Sanda Iacobas, Leonardo Lima Rocha, Fabio da Silva de Azevedo Fortes, Leandro Vairo, Fnu Nagajyothi, Antonio Carlos Campos de Carvalho, Herbert B. Tanowitz, and David C. Spray. "Transcriptomic alterations in Trypanosoma cruzi-infected cardiac myocytes." Microbes and Infection 11, no. 14-15 (December 2009): 1140–49. http://dx.doi.org/10.1016/j.micinf.2009.08.009.
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Han, Seong Kyu, Jungho Kong, Sanguk Kim, Jae‐Hoon Lee, and Dong‐Hoo Han. "Exomic and transcriptomic alterations of hereditary gingival fibromatosis." Oral Diseases 25, no. 5 (April 15, 2019): 1374–83. http://dx.doi.org/10.1111/odi.13093.
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Desi, Ng, and Yvonne Tay. "The Butterfly Effect of RNA Alterations on Transcriptomic Equilibrium." Cells 8, no. 12 (December 13, 2019): 1634. http://dx.doi.org/10.3390/cells8121634.
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Post-transcriptional regulation plays a key role in modulating gene expression, and the perturbation of transcriptomic equilibrium has been shown to drive the development of multiple diseases including cancer. Recent studies have revealed the existence of multiple post-transcriptional processes that coordinatively regulate the expression and function of each RNA transcript. In this review, we summarize the latest research describing various mechanisms by which small alterations in RNA processing or function can potentially reshape the transcriptomic landscape, and the impact that this may have on cancer development.
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Chehimi, Samar N., Richard C. Crist, and Benjamin C. Reiner. "Unraveling Psychiatric Disorders through Neural Single-Cell Transcriptomics Approaches." Genes 14, no. 3 (March 22, 2023): 771. http://dx.doi.org/10.3390/genes14030771.
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The development of single-cell and single-nucleus transcriptome technologies is enabling the unraveling of the molecular and cellular heterogeneity of psychiatric disorders. The complexity of the brain and the relationships between different brain regions can be better understood through the classification of individual cell populations based on their molecular markers and transcriptomic features. Analysis of these unique cell types can explain their involvement in the pathology of psychiatric disorders. Recent studies in both human and animal models have emphasized the importance of transcriptome analysis of neuronal cells in psychiatric disorders but also revealed critical roles for non-neuronal cells, such as oligodendrocytes and microglia. In this review, we update current findings on the brain transcriptome and explore molecular studies addressing transcriptomic alterations identified in human and animal models in depression and stress, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), schizophrenia, opioid use disorder, and alcohol and psychostimulant abuse. We also comment on potential future directions in single-cell and single-nucleus studies.
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Ashwin, Helen, Karin Seifert, Sarah Forrester, Najmeeyah Brown, Sandy MacDonald, Sally James, Dimitris Lagos, et al. "Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis." Wellcome Open Research 3 (October 29, 2018): 135. http://dx.doi.org/10.12688/wellcomeopenres.14867.1.
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Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of L. donovani-infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website, www.leishpathnet.org. Results: Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease. Conclusions: Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research.
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Ashwin, Helen, Karin Seifert, Sarah Forrester, Najmeeyah Brown, Sandy MacDonald, Sally James, Dimitris Lagos, et al. "Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis." Wellcome Open Research 3 (January 2, 2019): 135. http://dx.doi.org/10.12688/wellcomeopenres.14867.2.
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Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of L. donovani-infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website, www.leishpathnet.org. Results: Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease. Conclusions: Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research.
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Iacobas, Dumitru A., Sanda Iacobas, Marcia Urban-Maldonado, Eliana Scemes, and David C. Spray. "Similar Transcriptomic Alterations in Cx43 Knockdown and Knockout Astrocytes." Cell Communication & Adhesion 15, no. 1-2 (January 2008): 195–206. http://dx.doi.org/10.1080/15419060802014222.
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Smeets, Pascal J. H., Heleen M. de Vogel-van den Bosch, Peter H. M. Willemsen, Alphons P. Stassen, Torik Ayoubi, Ger J. van der Vusse, and Marc van Bilsen. "Transcriptomic analysis of PPARα-dependent alterations during cardiac hypertrophy." Physiological Genomics 36, no. 1 (December 2008): 15–23. http://dx.doi.org/10.1152/physiolgenomics.90296.2008.
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Peroxisome proliferator-activated receptor (PPAR)α regulates lipid metabolism at the transcriptional level and modulates the expression of genes involved in inflammation, cell proliferation, and differentiation. Although PPARα has been shown to mitigate cardiac hypertrophy, knowledge about underlying mechanisms and the nature of signaling pathways involved is fragmentary and incomplete. The aim of this study was to identify the processes and signaling pathways regulated by PPARα in hearts challenged by a chronic pressure overload by means of whole genome transcriptomic analysis. PPARα−/− and wild-type mice were subjected to transverse aortic constriction (TAC) for 28 days, and left ventricular gene expression profile was determined with Affymetrix GeneChip Mouse Genome 430 2.0 arrays containing >45,000 probe sets. In unchallenged hearts, the mere lack of PPARα resulted in 821 differentially expressed genes, many of which are related to lipid metabolism and immune response. TAC resulted in a more pronounced cardiac hypertrophy and more extensive changes in gene expression (1,910 and 312 differentially expressed genes, respectively) in PPARα−/− mice than in wild-type mice. Many of the hypertrophy-related genes were related to development, signal transduction, actin filament organization, and collagen synthesis. Compared with wild-type hypertrophied hearts, PPARα−/− hypertrophied hearts revealed enrichment of gene clusters related to extracellular matrix remodeling, immune response, oxidative stress, and inflammatory signaling pathways. The present study therefore demonstrates that, in addition to lipid metabolism, PPARα is an important modulator of immune and inflammatory response in cardiac muscle.
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Shao, Xuelian, Yu Fu, Jinmin Ma, Xueyu Li, Chenqi Lu, and Ruilin Zhang. "Functional alterations and transcriptomic changes during zebrafish cardiac aging." Biogerontology 21, no. 5 (May 5, 2020): 637–52. http://dx.doi.org/10.1007/s10522-020-09881-z.
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Teng, Da, Keiji Ueda, and Tomoyuki Honda. "Impact of Borna Disease Virus Infection on the Transcriptome of Differentiated Neuronal Cells and Its Modulation by Antiviral Treatment." Viruses 15, no. 4 (April 10, 2023): 942. http://dx.doi.org/10.3390/v15040942.
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Borna disease virus (BoDV-1) is a highly neurotropic RNA virus that causes neurobehavioral disturbances such as abnormal social activities and memory impairment. Although impairments in the neural circuits caused by BoDV-1 infection induce these disturbances, the molecular basis remains unclear. Furthermore, it is unknown whether anti-BoDV-1 treatments can attenuate BoDV-1-mediated transcriptomic changes in neuronal cells. In this study, we investigated the effects of BoDV-1 infection on neuronal differentiation and the transcriptome of differentiated neuronal cells using persistently BoDV-1-infected cells. Although BoDV-1 infection did not have a detectable effect on intracellular neuronal differentiation processes, differentiated neuronal cells exhibited transcriptomic changes in differentiation-related genes. Some of these transcriptomic changes, such as the decrease in the expression of apoptosis-related genes, were recovered by anti-BoDV-1 treatment, while alterations in the expression of other genes remained after treatment. We further demonstrated that a decrease in cell viability induced by differentiation processes in BoDV-1-infected cells can be relieved with anti-BoDV-1 treatment. This study provides fundamental information regarding transcriptomic changes after BoDV-1 infection and the treatment in neuronal cells.
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Ritter, M., C. Blume, B. Patel, Y. Tang, A. Patel, N. Berghaus, Z. Seferbekova, et al. "OS10.8.A APPLICATIONS OF NOVEL FFPE BASED TECHNOLOGIES FOR THE DIAGNOSTICS OF GLIOMAS." Neuro-Oncology 25, Supplement_2 (September 1, 2023): ii23. http://dx.doi.org/10.1093/neuonc/noad137.068.
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Abstract BACKGROUND Due to the lack of consistent tumour-cell specific markers, the diffuse brain invasion of glioblastoma (GB) presents a significant diagnostic challenge, especially for specimens with a low tumour cell fraction or scarce tissue. The only common alteration found in most GB is the gain of chromosome 7 and loss of chromosome 10. The emergence of new technologies such as spatial and single nucleus transcriptomics that allow for detection of copy number alterations (CNVs) may allow us to push the diagnostic boundaries. MATERIAL AND METHODS We performed 10x Visium spatial transcriptomic analysis of FFPE tissue from bulk resections of 14 FFPE GB and stereotactic biopsies of 6 GB, 7 IDH mutant astrocytomas, 4 oligodendrogliomas and 1 diffuse glioma NOS. Visium tissue spots were then deconvolved using data from single nucleus transcriptomic data from nuclei isolated from FFPE tissue. Fresh frozen and FFPE single nucleus transcriptomic libraries were also generated from 4 GB with matching fresh-frozen and FFPE tissue available. RESULTS The infiltration zone, the tumour core and healthy brain tissue could be differentiated using the inferred CNVs of chromosome 7 and chromosome 10. Additionally, inferred CNVs of tissue fragments smaller than 1 mm2 were in accordance with Infinium MethylationEPIC array analysis (a well-established method for CNV detection) from the same tumour tissue. Using the spatial transcriptomics approach, the loss of chromosome 1p and 19q, which is characteristic for oligodendroglioma was also detected. To overcome the low resolution of Visium, deconvolution approaches using a single cell dataset can be used to determine the tumour content of a given tissue more precisely. To test if the single nuclei data from FFPE samples is suitable for deconvolution of spatial transcriptomics, we compared fresh-frozen and FFPE single nuclei data from matching tumours. As expected, FFPE and fresh frozen nuclei clustered together according to cell types and tumours in the UMAP space. CONCLUSION Spatial transcriptomics can be useful for brain tumour diagnostic workup, especially in cases where a limited amount of tissue prevents analysis by standard molecular diagnostic METHODS . Additionally, CNVs inferred from the spatial data as well as the spatial expression of marker genes help to better distinguish tumour infiltration zones from the core tumour and healthy brain tissue in the case of GB. This analysis can be further supported by deconvolution with a reference set generated from single nucleus transcriptomic analysis of FFPE tissue.
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Park, Sangmin, Aeyung Kim, Gunhyuk Park, Ojin Kwon, Sangsoo Park, Horyong Yoo, and Junghee Jang. "Investigation of Therapeutic Response Markers for Acupuncture in Parkinson’s Disease: An Exploratory Pilot Study." Diagnostics 11, no. 9 (September 17, 2021): 1697. http://dx.doi.org/10.3390/diagnostics11091697.
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In this preliminary pilot study, we investigated the specific genes implicated in the therapeutic response to acupuncture in patients with Parkinson’s disease (PD). Transcriptome alterations following acupuncture in blood samples collected during our previous clinical trial were analyzed along with the clinical data of six patients with PD, of which a representative patient was selected for transcriptomic analysis following acupuncture. We also examined the changes in the expression of PD biomarker genes known to be dysregulated in both the brain and blood of patients with PD. We validated these gene expression changes using quantitative real-time polymerase chain reaction (qPCR) in the blood of the remaining five patients with PD who received acupuncture treatment. Following acupuncture treatment, the transcriptomic alterations in the representative patient were similar to those induced by dopaminergic therapy. Among the PD biomarkers, ankyrin repeat domain 22 (ANKRD22), upregulated following dopaminergic therapy, and synapsin 1 (SYN1), a common gene marker for synaptic dysfunction in PD, were upregulated following acupuncture. These alterations correlated with changes in gait parameters in patients with PD. Our data suggest ANKRD22 and SYN1 as potential biomarkers to predict/monitor therapeutic responses to acupuncture in patients with PD, especially in those with gait disturbance. Further research is needed to confirm these findings in a large sample of patients with PD.
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de Sousa, Nídia, Gustavo Rodriguez-Esteban, Ivan Colagè, Paolo D’Ambrosio, Jack van Loon, Emili Saló, Teresa Adell, and Gennaro Auletta. "Transcriptomic Analysis of Planarians under Simulated Microgravity or 8 g Demonstrates That Alteration of Gravity Induces Genomic and Cellular Alterations That Could Facilitate Tumoral Transformation." International Journal of Molecular Sciences 20, no. 3 (February 8, 2019): 720. http://dx.doi.org/10.3390/ijms20030720.
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The possibility of humans to live outside of Earth on another planet has attracted the attention of numerous scientists around the world. One of the greatest difficulties is that humans cannot live in an extra-Earth environment without proper equipment. In addition, the consequences of chronic gravity alterations in human body are not known. Here, we used planarians as a model system to test how gravity fluctuations could affect complex organisms. Planarians are an ideal system, since they can regenerate any missing part and they are continuously renewing their tissues. We performed a transcriptomic analysis of animals submitted to simulated microgravity (Random Positioning Machine, RPM) (s-µg) and hypergravity (8 g), and we observed that the transcriptional levels of several genes are affected. Surprisingly, we found the major differences in the s-µg group. The results obtained in the transcriptomic analysis were validated, demonstrating that our transcriptomic data is reliable. We also found that, in a sensitive environment, as under Hippo signaling silencing, gravity fluctuations potentiate the increase in cell proliferation. Our data revealed that changes in gravity severely affect genetic transcription and that these alterations potentiate molecular disorders that could promote the development of multiple diseases such as cancer.
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Kim, Tae Kyoo, Sangjoon Lee, and Heh-In Im. "Quantitative Sequencing Analysis of the Striatal Transcriptome in a Mouse Model of Alzheimer Disease." International Neurourology Journal 26, Suppl 2 (November 30, 2022): S117–125. http://dx.doi.org/10.5213/inj.2244256.128.
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Purpose: The purpose of this study was to analyze the transcriptomic changes in the striatum of amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and uncover its association with the methyl-CpG binding protein 2 (MeCP2) mediated-changes in striatal epigenetic signature during Alzheimer disease (AD) pathological progression.Methods: To observe transcriptomic alterations in the striatum before the onset of cognitive impairment in APP/PS1 mice, quantitative 3’mRNA sequencing was performed with RNA extracted from the striatum of 6-month-old and 12-month-old wildtype and APP/PS1 mice. In addition, chromatin immunoprecipitation sequencing was conducted with the DNA from wildtype and APP/PS1 mice of the same age as aforementioned. For transcriptomic analysis, comparison terms were constructed based on aging and transgene expression—normal-aging (12-month-old wildtype/6-month-old wildtype), early-AD (6-month-old APP/PS1/6-month-old wildtype), and late-AD (12-month-old APP/PS1/6-month-old wildtype). To compare the changes in biological pathways and networks, we analyzed gene lists from each comparison term via bioinformatics tools including DAVID (Database for Annotation, Visualization, and Integrated Discovery), STRING (Search Tool for the Retrieval of Interacting Genes/Proteins), and SynGO (Synaptic Gene Ontologies). Furthermore, to assume the effect MeCP2 in AD pathological conditions may have on the transcriptome regulation, analysis of the common genes from Quant-Seq and MeCP2-ChIP-Seq was performed.Results: Enriched pathways including immune system and inflammatory response were confirmed in normal- aging and lateAD, respectively. In particular, enriched pathways of gene expression regulation, transcriptional regulation, and protein catabolic pathways were found to be significantly altered in early-AD. MeCP2-bound genes that were significantly altered in the transcriptome were suggested to be target genes that have a role in the striatum of the early-stage AD model.Conclusions: This study confirmed that the alteration of the striatal transcriptomic profile in APP/PS1 mice was involved with several biological pathways. Additionally, comparative analysis of the transcriptomic changes and the MeCP2 bound regions found that a group of differentially expressed genes may be regulated under the epigenetic control of MeCP2.
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Kanata, Eirini, Franc Llorens, Dimitra Dafou, Athanasios Dimitriadis, Katrin Thüne, Konstantinos Xanthopoulos, Nikolaos Bekas, et al. "RNA editing alterations define manifestation of prion diseases." Proceedings of the National Academy of Sciences 116, no. 39 (September 6, 2019): 19727–35. http://dx.doi.org/10.1073/pnas.1803521116.
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Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt–Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-PRNP129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.
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Andersson, Hampus, Aastha Sobti, David Gomez Jimenez, Yago Pico de Coaña, Sumeet Vijay Ambarkhane, Karin Hägerbrand, Karin Enell Smith, Malin Lindstedt, and Peter Ellmark. "Early Pharmacodynamic Changes Measured Using RNA Sequencing of Peripheral Blood from Patients in a Phase I Study with Mitazalimab, a Potent CD40 Agonistic Monoclonal Antibody." Cells 12, no. 19 (September 27, 2023): 2365. http://dx.doi.org/10.3390/cells12192365.
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CD40-targeting therapies can enhance the dendritic cell priming of tumor-specific T cells and repolarize intratumoral macrophages to alleviate the tumoral immunosuppressive environment and remodel the extracellular matrix. Mitazalimab is a potent agonistic CD40 monoclonal IgG1 antibody currently under clinical development. This study used RNA sequencing of blood samples from a subset of patients from a Phase I trial with mitazalimab (NCT02829099) to assess peripheral pharmacodynamic activity. We found that mitazalimab induced transient peripheral transcriptomic alterations (at 600 µg/kg and 900 µg/kg dose administered intravenously), which mainly were attributed to immune activation. In particular, the transcriptomic alterations showed a reduction in effector cells (e.g., CD8+ T cells and natural killer cells) and B cells peripherally with the remaining cells (e.g., dendritic cells, monocytes, B cells, and natural killer cells) showing transcription profiles consistent with activation. Lastly, distinct patient subgroups based on the pattern of transcriptomic alterations could be identified. In summary, the data presented herein reinforce the anticipated mode of action of mitazalimab and support its ongoing clinical development.
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Dunnick, June K., Keith R. Shockley, Daniel L. Morgan, Gregory S. Travlos, Kevin Gerrish, Thai-Vu T. Ton, Ralph Wilson, et al. "Hepatic Transcriptomic Patterns in the Neonatal Rat After Pentabromodiphenyl Ether Exposure." Toxicologic Pathology 48, no. 2 (December 12, 2019): 338–49. http://dx.doi.org/10.1177/0192623319888433.
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Human exposure to pentabromodiphenyl ether (PBDE) mixture (DE-71) and its PBDE-47 congener can occur both in utero and during lactation. Here, we tested the hypothesis that PBDE-induced neonatal hepatic transcriptomic alterations in Wistar Han rat pups can inform on potential toxicity and carcinogenicity after longer term PBDE exposures. Wistar Han rat dams were exposed to either DE-71 or PBDE-47 daily from gestation day (GD 6) through postnatal day 4 (PND 4). Total plasma thyroxine (T4) was decreased in PND 4 pups. In liver, transcripts for CYPs and conjugation enzymes, Nrf2, and ABC transporters were upregulated. In general, the hepatic transcriptomic alterations after exposure to DE-71 or PBDE-47 were similar and provided early indicators of oxidative stress and metabolic alterations, key characteristics of toxicity processes. The transcriptional benchmark dose lower confidence limits of the most sensitive biological processes were lower for PBDE-47 than for the PBDE mixture. Neonatal rat liver transcriptomic data provide early indicators on molecular pathway alterations that may lead to toxicity and/or carcinogenicity if the exposures continue for longer durations. These early toxicogenomic indicators may be used to help prioritize chemicals for a more complete toxicity and cancer risk evaluation.
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Li, Jingyun, Rui Wang, Xin Zhou, Wendong Wang, Shuai Gao, Yunuo Mao, Xinglong Wu, et al. "Genomic and transcriptomic profiling of carcinogenesis in patients with familial adenomatous polyposis." Gut 69, no. 7 (November 19, 2019): 1283–93. http://dx.doi.org/10.1136/gutjnl-2019-319438.
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ObjectiveFamilial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of adenomas at different evolutionary stages in the colon and rectum that will inevitably progress to adenocarcinomas if left untreated. Here, we investigated the genetic alterations and transcriptomic transitions from precancerous adenoma to carcinoma.DesignWhole-exome sequencing, whole-genome sequencing and single-cell RNA sequencing were performed on matched adjacent normal tissues, multiregionally sampled adenomas at different stages and carcinomas from six patients with FAP and one patient with MUTYH-associated polyposis (n=56 exomes, n=56 genomes and n=8,757 single cells). Genomic alterations (including copy number alterations and somatic mutations), clonal architectures and transcriptome dynamics during adenocarcinoma carcinogenesis were comprehensively investigated.ResultsGenomic evolutionary analysis showed that adjacent lesions from the same patient with FAP can originate from the same cancer-primed cell. In addition, the tricarboxylic acid cycle pathway was strongly repressed in adenomas and was then slightly alleviated in carcinomas. Cells from the ‘normal’ colon epithelium of patients with FAP already showed metabolic reprogramming compared with cells from the normal colon epithelium of patients with sporadic colorectal cancer.ConclusionsThe process described in the previously reported field cancerisation model also occurs in patients with FAP and can contribute to the formation of adjacent lesions in patients with FAP. Reprogramming of carbohydrate metabolism has already occurred at the precancerous adenoma stage. Our study provides an accurate picture of the genomic and transcriptomic landscapes during the initiation and progression of carcinogenesis, especially during the transition from adenoma to carcinoma.
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Zhu, Tao, Anthony P. Brown, Lucy P. Cai, Gerald Quon, and Hong Ji. "Single-Cell RNA-Seq Analysis Reveals Lung Epithelial Cell Type-Specific Responses to HDM and Regulation by Tet1." Genes 13, no. 5 (May 14, 2022): 880. http://dx.doi.org/10.3390/genes13050880.
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Tet1 protects against house dust mite (HDM)-induced lung inflammation in mice and alters the lung methylome and transcriptome. In order to explore the role of Tet1 in individual lung epithelial cell types in HDM-induced inflammation, we established a model of HDM-induced lung inflammation in Tet1 knockout and littermate wild-type mice, then studied EpCAM+ lung epithelial cells using single-cell RNA-seq analysis. We identified eight EpCAM+ lung epithelial cell types, among which AT2 cells were the most abundant. HDM challenge altered the relative abundance of epithelial cell types and resulted in cell type-specific transcriptomic changes. Bulk and cell type-specific analysis also showed that loss of Tet1 led to the altered expression of genes linked to augmented HDM-induced lung inflammation, including alarms, detoxification enzymes, oxidative stress response genes, and tissue repair genes. The transcriptomic regulation was accompanied by alterations in TF activities. Trajectory analysis supports that HDM may enhance the differentiation of AP and BAS cells into AT2 cells, independent of Tet1. Collectively, our data showed that lung epithelial cells had common and unique transcriptomic signatures of allergic lung inflammation. Tet1 deletion altered transcriptomic networks in various lung epithelial cells, which may promote allergen-induced lung inflammation.
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Ranganathan, Prathibha, H. C. Harsha, and Akhilesh Pandey. "Molecular Alterations in Exocrine Neoplasms of the Pancreas." Archives of Pathology & Laboratory Medicine 133, no. 3 (March 1, 2009): 405–12. http://dx.doi.org/10.5858/133.3.405.
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Abstract Context.—Pancreatic cancer is one of the leading causes of cancer-related deaths. Most cases are diagnosed at an advanced stage when the disease is beyond surgical intervention. Molecular studies during the past decade have contributed greatly to our understanding of this disease. Various germ-line and somatic mutations associated with pancreatic cancers have been characterized, along with abnormal variations in the gene expression patterns. A thorough characterization of molecular alterations such as genetic and epigenetic changes, alterations in the expression of genes and changes in proteins, and posttranslational modifications in pancreatic cancer could lead to a better understanding of its pathogenesis. Objective.—To provide an overview of the various molecular alterations in pancreatic cancer and the methodologies used to catalog such alterations. Data Sources.—Published studies about various molecular alterations at the genomic, epigenetic, transcriptomic, and proteomic levels in pancreatic cancer. Conclusions.—The available data from pancreatic cancer suggests that there are a large number of molecular alterations at genomic, epigenetic, transcriptomic, and proteomic levels. It is now possible to initiate a systems approach to studying pancreatic cancer especially in light of newer initiatives to dissect the pancreatic cancer genome.
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Cheng, Yu-Hao, Shu-Fen Liu, Jing-Cheng Dong, and Qin Bian. "Transcriptomic alterations underline aging of osteogenic bone marrow stromal cells." World Journal of Stem Cells 13, no. 1 (January 26, 2021): 128–38. http://dx.doi.org/10.4252/wjsc.v13.i1.128.
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Machlovi, Saima I., Sarah M. Neuner, Brittany M. Hemmer, Riana Khan, Yiyuan Liu, Min Huang, Jeffrey D. Zhu, et al. "APOE4 confers transcriptomic and functional alterations to primary mouse microglia." Neurobiology of Disease 164 (March 2022): 105615. http://dx.doi.org/10.1016/j.nbd.2022.105615.
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Fernández-Medarde, Alberto, Rima Barhoum, Raquel Riquelme, Angel Porteros, Alejandro Núñez, Alberto de Luis, Javier de las Rivas, Pedro de la Villa, Isabel Varela-Nieto, and Eugenio Santos. "RasGRF1 disruption causes retinal photoreception defects and associated transcriptomic alterations." Journal of Neurochemistry 110, no. 2 (July 2009): 641–52. http://dx.doi.org/10.1111/j.1471-4159.2009.06162.x.
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HATAKEYAMA, Keiichi, Takeshi NAGASHIMA, Keiichi OHSHIMA, Sumiko OHNAMI, Shumpei OHNAMI, Yuji SHIMODA, Akane NARUOKA, et al. "Impact of somatic mutations and transcriptomic alterations on cancer aneuploidy." Biomedical Research 44, no. 5 (September 27, 2023): 187–97. http://dx.doi.org/10.2220/biomedres.44.187.
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Podstawski, Przemysław, Marcin Samiec, Maria Skrzyszowska, Tomasz Szmatoła, Ewelina Semik-Gurgul, and Katarzyna Ropka-Molik. "The Induced Expression of BPV E4 Gene in Equine Adult Dermal Fibroblast Cells as a Potential Model of Skin Sarcoid-like Neoplasia." International Journal of Molecular Sciences 23, no. 4 (February 10, 2022): 1970. http://dx.doi.org/10.3390/ijms23041970.
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The equine sarcoid is one of the most common neoplasias in the Equidae family. Despite the association of this tumor with the presence of bovine papillomavirus (BPV), the molecular mechanism of this lesion has not been fully understood. The transgenization of equine adult cutaneous fibroblast cells (ACFCs) was accomplished by nucleofection, followed by detection of molecular modifications using high-throughput NGS transcriptome sequencing. The results of the present study confirm that BPV-E4- and BPV-E1^E4-mediated nucleofection strategy significantly affected the transcriptomic alterations, leading to sarcoid-like neoplastic transformation of equine ACFCs. Furthermore, the results of the current investigation might contribute to the creation of in vitro biomedical models suitable for estimating the fates of molecular dedifferentiability and the epigenomic reprogrammability of BPV-E4 and BPV-E4^E1 transgenic equine ACFC-derived sarcoid-like cell nuclei in equine somatic cell-cloned embryos. Additionally, these in vitro models seem to be reliable for thoroughly recognizing molecular mechanisms that underlie not only oncogenic alterations in transcriptomic signatures, but also the etiopathogenesis of epidermal and dermal sarcoid-dependent neoplastic transformations in horses and other equids. For those reasons, the aforementioned transgenic models might be useful for devising clinical treatments in horses afflicted with sarcoid-related neoplasia of cutaneous and subcutaneous tissues.
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Chen, Chen, Guozhong Zhao, Wei Chen, and Benheng Guo. "Metabolism of Fructooligosaccharides in Lactobacillus plantarum ST-III via Differential Gene Transcription and Alteration of Cell Membrane Fluidity." Applied and Environmental Microbiology 81, no. 22 (August 28, 2015): 7697–707. http://dx.doi.org/10.1128/aem.02426-15.
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ABSTRACTAlthough fructooligosaccharides (FOS) can selectively stimulate the growth and activity of probiotics and beneficially modulate the balance of intestinal microbiota, knowledge of the molecular mechanism for FOS metabolism by probiotics is still limited. Here a combined transcriptomic and physiological approach was used to survey the global alterations that occurred during the logarithmic growth ofLactobacillus plantarumST-III using FOS or glucose as the sole carbon source. A total of 363 genes were differentially transcribed; in particular, two gene clusters were induced by FOS. Gene inactivation revealed that both of the clusters participated in the metabolism of FOS, which were transported across the membrane by two phosphotransferase systems (PTSs) and were subsequently hydrolyzed by a β-fructofuranosidase (SacA) in the cytoplasm. Combining the measurements of the transcriptome- and membrane-related features, we discovered that the genes involved in the biosynthesis of fatty acids (FAs) were repressed in cells grown on FOS; as a result, the FA profiles were altered by shortening of the carbon chains, after which membrane fluidity increased in response to FOS transport and utilization. Furthermore, incremental production of acetate was observed in both the transcriptomic and the metabolic experiments. Our results provided new insights into gene transcription, the production of metabolites, and membrane alterations that could explain FOS metabolism inL. plantarum.
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Kazandjian, Suzanne, Emmanuelle Rousselle, Matthew Dankner, David W. Cescon, Anna Spreafico, Kim Ma, Petr Kavan, Gerald Batist, and April A. N. Rose. "The Clinical, Genomic, and Transcriptomic Landscape of BRAF Mutant Cancers." Cancers 16, no. 2 (January 19, 2024): 445. http://dx.doi.org/10.3390/cancers16020445.
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Background: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients. Methods: Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas. Results: BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs. Class 2/3 mutations (RAS, NF1). Across all tumor types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/β-catenin. Pathway analysis revealed enrichment of WNT/β-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs. 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs. younger (38% vs. 15% p < 0.0001), except in CRC (15% vs. 30% q = 0.0001). Black race was associated with non-V600 BRAF alterations (OR: 1.58; p < 0.0001). Conclusions: Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations.
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Mullighan, Charles G., Ryan Morin, Jinghui Zhang, Martin Hirst, Yongjun Zhao, Chunhua Yan, Richard Finney, et al. "Next Generation Transcriptomic Resequencing Identifies Novel Genetic Alterations in High-Risk (HR) Childhood Acute Lymphoblastic Leukemia (ALL): A Report From the Children's Oncology Group (COG) HR ALL TARGET Project." Blood 114, no. 22 (November 20, 2009): 704. http://dx.doi.org/10.1182/blood.v114.22.704.704.
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Abstract Abstract 704 Relapsed ALL is a leading cause of childhood cancer death, and the biologic factors responsible for relapse are poorly understood, particularly in cases lacking sentinel chromosomal alterations. Recent studies from the Children's Oncology Group high risk ALL TARGET (Therapeutically Applicable Research to Generate Effective Targets) project that used genome-wide profiling of DNA copy number alterations and candidate gene resequencing have identified novel biomarkers of relapse (IKZF1 alteration) and therapeutic targets (JAK mutation). As a complementary approach to identify novel genomic alterations, we used second generation sequencing technology to sequence the tumor transcriptome of three cases from the COG P9906 high risk (HR) B-precursor ALL trial. The selected cases had previously been profiled by high resolution SNP and gene expression arrays and candidate gene resequencing, and lacked known sentinel chromosomal rearrangements. Each case bore features previously associated with poor treatment outcome: a gene expression profile (GEP) similar to that of BCR-ABL1 positive ALL (all cases), deletion or mutation of IZKF1 (two cases), and JAK mutation (JAK2 R867Q, one case). cDNA libraries were generated from poly-A enriched RNA and 36-50 base paired-end sequencing performed using the Illumina Genome Analyzer. Sequence alignment, variant detection and fusion transcript identification were performed using custom scripts and multiple published reference alignment and de-novo assembly algorithms. A total of 115-127 million total and 93-97 million mapped, unique reads were obtained per case. The average depth of coverage of Refseq exons ranged from 25- to 39-fold. A minimum of 5 putative fusion transcripts were identified per case, some of which were known from prior transcriptome sequencing to be recurring false positives. However, a novel transcript with an in-frame fusion of exon 9 of the striatin gene STRN3 to exon 18 of JAK2 (STRN3-JAK2) was identified in one case, and confirmed by RT-PCR and direct Sanger sequencing. Fusion of NUP214 to ABL1 was identified in a second case and also confirmed by direct sequencing. The NUP214-ABL1 rearrangement has previously only been identified in T-lineage ALL. In this case, the translocation was accompanied by amplification of the NUP214-ABL1 region at 9q. RT-PCR screening of an additional 60 high-risk ALL cases with GEP data suggestive of kinase alteration identified an additional two cases with NUP214-ABL1 fusion, each of which was accompanied by NUP214-ABL1 amplification. These two novel fusion transcripts are predicted to result in aberrant kinase signaling, and are candidates for novel therapeutic intervention. Both occurred in ALLs with a BCR-ABL1-like GEP that lacked known JAK mutations, suggesting that additional novel activating kinase mutations can be discovered via detailed sequence analysis of the 50% of BCR-ABL1-like ALLs that do not have JAK mutations. Aberrant splice variants and truncated isoforms arising from DNA copy number alterations, including internal deletions of PAX5 and truncating deletions of BTG1 were also identified using the transcriptome sequencing data. In addition, these data identified over 400 candidate non-synonymous single nucleotide and insertion/deletion variations in each patient. Known mutations involving PAX5, IKZF1 and JAK2 were robustly identified. Whole genome sequencing of matched normal DNA is underway to remove germline variation from the list of putative variants, and transcriptomic sequencing of additional cases of HR childhood ALL are being performed. Together, these data indicate that transcriptomic sequencing is a powerful method to identify novel genetic alterations in ALL, and may be used to identify novel targets for therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.
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Montfort-Ferré, D., A. Boronat-Toscano, J. F. Sánchez-Herrero, A. Caro, M. Menacho, I. Vañó-Segarra, M. Martí, et al. "P074 Inflammatory Environment-Induced Transcriptomic Alterations in Crohn's Disease Adipose Stem Cells." Journal of Crohn's and Colitis 18, Supplement_1 (January 1, 2024): i344—i345. http://dx.doi.org/10.1093/ecco-jcc/jjad212.0204.
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Abstract Background Crohn’s disease (CD) is characterised by expansion of mesenteric adipose tissue, called creeping fat, which seems to be directly related to disease activity. Adipose stem cells (ASCs) isolated from the creeping fat of CD patients exhibit dysfunction, featuring impaired adipogenesis and an intensely pro-inflammatory phenotype. This study aims to explore the transcriptome of ASCs isolated from active and inactive CD subjects in comparison with healthy subjects, seeking key markers of this dysregulation. Methods Patients were recruited at Hospital Joan XXIII of Tarragona and Hospital Vall d’Hebron of Barcelona in accordance with the principles of the Helsinki Declaration. Transcriptome profiling was performed in ASCs isolated from adipose-tissue biopsies of visceral origin: CF and hMES in Crohn subjects (n=7, each) and hMES in inactive CD patients (n=7) and healthy control subjects (n=7). Groups were matched by age, gender, and BMI. Finally, we examined the pathways involving the differentially expressed gene (DEGs) in ASCs isolated from patients with CD with different clinical activity by gene set enrichment analysis (GSEA). Results Patients with CD across different clinical activity stages exhibited similar transcriptome patterns, indicating persistent ASC dysregulation even during remission state (Fig 1A). ASCs isolated from both creeping fat and mesenteric adipose tissue distant from intestinal damage displayed similar dysregulation, implying a global dysregulation of all mesenteric fat in CD. Specifically, transcriptomic analysis identified significant dysregulation of the NK2 Homeobox 3 (NKX2-3) gene in ASCs from active CD patients. Although higher NKX2-3 expression has been associated with B cells and intestinal tissues in CD1-3, our study is the first to link elevated expression of this gene also to creeping fat. Pathway enrichment analysis revealed significant enrichment in oxidative stress and immune response pathways in active CD (Fig 1B). Furthermore, our findings indicated also an elevated NKX2-3 expression in ASCs of inactive CD compared to controls, with oxidative stress pathway up-regulation (Fig 1C). Notably, no significant DEGs were found between ASCs from active and inactive CD groups (Fig 1D), suggesting a similar profile in both states. Conclusion Our study reveals profound ASC dysregulation in CD, in both active and inactive phases. Elevated NKX2-3 expression, previously associated with increased risk of complications in IBD, is now demonstrated in the mesenteric adipose tissue, persisting even in inactive CD patients. Ref: 1. Yamazaki K, et al Gut. 2009 Feb;58(2):228-32. 2. Yu W, et al. J Crohn’s Colitis. 2009 Sep;3(3):189-95. 3. Hong SN et al. Gut. 2016 May;65(5):788-96.
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Dang, Weiwei, Luyang Sun, and Brenna McCauley. "ALTERED SUPER ENHANCER – PROMOTER INTERACTIONS MEDIATED BY YY1 UNDERLIE AGE-INDUCED TRANSCRIPTOME." Innovation in Aging 6, Supplement_1 (November 1, 2022): 733. http://dx.doi.org/10.1093/geroni/igac059.2670.
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Abstract Significant changes in transcriptome during aging have been observed in various tissues and cell types, even at the single-cell level. However, the molecular mechanisms that underlie these changes remain poorly understood. Using an ex vivo mesenchymal stem cells (MSC) replicative aging model and Hi-C technology, we discovered that, rather than large-scale changes in chromosome conformation, alterations to super enhancer – promoter looping interactions had the best positive correlation with age-associated transcriptome. Furthermore, we found evidence that these age-induced transcriptomic changes are mediated by YY1, a key regulator of promoter-enhancer looping. This work, for the first time, unveiled a molecular mechanism elucidating the changes in transcription during aging.
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Kong, Say Li, Huipeng Li, Joyce A. Tai, Elise T. Courtois, Huay Mei Poh, Dawn Pingxi Lau, Yu Xuan Haw, et al. "Concurrent Single-Cell RNA and Targeted DNA Sequencing on an Automated Platform for Comeasurement of Genomic and Transcriptomic Signatures." Clinical Chemistry 65, no. 2 (February 1, 2019): 272–81. http://dx.doi.org/10.1373/clinchem.2018.295717.
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Abstract BACKGROUND The comeasurement of both genomic and transcriptomic signatures in single cells is of fundamental importance to accurately assess how the genetic information correlates with the transcriptomic phenotype. However, existing technologies have low throughput and laborious work flows. METHODS We developed a new method for concurrent sequencing of the transcriptome and targeted genomic regions (CORTAD-seq) within the same single cell on an automated microfluidic platform. The method was compatible with the downstream library preparation, allowing easy integration into existing next-generation sequencing work flows. We incorporated a single-cell bioinformatics pipeline for transcriptome and mutation analysis. RESULTS As proof of principle, we applied CORTAD-seq to lung cancer cell lines to dissect the cellular consequences of mutations that result in resistance to targeted therapy. We obtained a mean detection of 6000 expressed genes and an exonic rate of 50%. The targeted DNA-sequencing data achieved a 97.8% detection rate for mutations and allowed for the identification of copy number variations and haplotype construction. We detected expression signatures of tyrosine kinase inhibitor (TKI) resistance, epidermal growth factor receptor (EGFR) amplification, and expansion of the T790M mutation among resistant cells. We also identified characteristics for TKI resistance that were independent of EGFR T790M, indicating that other alterations are required for resistance in this context. CONCLUSIONS CORTAD-seq allows assessment of the interconnection between genetic and transcriptomic changes in single cells. It is operated on an automated, commercially available single-cell isolation platform, making its implementation straightforward.
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Ahmad, Omar, Rebecca Chapman, Lisa Storer, Li Luo, Linda Resar, Kenneth Cohen, Richard Grundy, and Anbarasu Lourdusamy. "DNA methylation and transcriptomic alterations define distinct groups in pediatric spinal ependymoma." Neuro-Oncology 21, Supplement_4 (October 2019): iv6. http://dx.doi.org/10.1093/neuonc/noz167.025.
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Abstract In contrast, compared to adults, spinal ependymomas (SEPN) are less common in childhood and adolescents. Children with these tumours are likely to experience a more aggressive disease course, with a higher rate of local failure, and a higher rate of metastasis. Presently the molecular basis of SEPN is poorly characterized. Therefore, we have analyzed 29 SEPN tumour samples from pediatric patients (female: 11, male: 15; age range: 4 – 21 years) and performed DNA methylation (n=28) and transcriptome profiling (n=29). Unsupervised analysis of methylation data reliably separated these tumours into two distinct groups: one group covering all myxopapillary ependymomas (MPE) and a second group dominated by grade II SPENs (SP-EPN). We identified 242 differentially methylated regions between these two groups, of which 56% showed high methylation levels in MPE, including 22 regions localized on chromosome 6. Genome-wide copy number analysis using methylation data showed differences in numbers and pattern of DNA copy number alterations between these groups. Gain of chromosome 20 (39%) followed by loss of chromosomes 6 (28%), 10 (28%), and 13 (28%) were detected in the MPE group, whereas loss of chromosome 22 was frequent (60%) in the SP-EPN group. Transcriptomic analysis showed that genes associated with oxidative phosphorylation, TCA cycle components, electron transport, and Interferon-gamma production characterize the MPE group whereas potassium ion import and regulation of astrocyte differentiation characterize the SP-EPN group. Taken together, this data suggest that mitochondrial oxidative phosphorylation may drive the regulation of energy metabolism of MPE tumours.
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Sauta, Elisabetta, Matteo Zampini, Daniele Dall'Olio, Claudia Sala, Gabriele Todisco, Erica Travaglino, Luca Lanino, et al. "Combining Gene Mutation with Transcriptomic Data Improves Outcome Prediction in Myelodysplastic Syndromes." Blood 142, Supplement 1 (November 28, 2023): 1863. http://dx.doi.org/10.1182/blood-2023-186222.
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Background and Aim. Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by peripheral blood cytopenias and risk of progression to acute myeloid leukemia (AML). Disease management is challenged by heterogeneity in clinical courses and survival probability. Recently, the genomic screening integration (by Molecular International Prognostic Scoring System, IPSS-M) into patient's assessment has resulted into a significant improvement in predicting clinical outcomes compared to the conventional prognostic score (Revised IPSS, IPSS-R). Many of the consequences of genetic and cytogenetic alterations will affect gene expression by means of transcriptional and epigenetic instability and altered microenviromental signaling. The aim of this project conducted by GenoMed4All and Synthema EU consortia is to link genomic information with transcriptomic data for possibly improving the prediction of clinical outcomes in MDS patients. Patients and Methods.Clinical, cytogenetic, genomic (somatic mutations screening of 31 target genes) and transcriptomic (bulk RNA-seq of CD34 + bone marrow cells) data were collected at diagnosis in 389 MDS patients. Transcriptomic and genomic profiles were processed and the former were normalized before Principal Component Analysis (PCA) dimensionality reduction to mine the interdependency of expression-wide perturbation and recurrent genomic alterations. The prognostic impacts of genetic, cytogenetic, transcriptomic, clinical and demographic features were assessed with a penalized Cox's proportional hazards model [Gerstung M et al, Nat Commun. 2015. 6, 5901] considering the Overall Survival (OS) as primary end point. A 5-fold cross-validating (CV) scheme was exploited to control bias in risk estimation. Model accuracy was assessed using Harrell's concordance index (C-index). An independent validation of the results on 202 patients was planned. Results.We first processed each data layer assessing data robustness, removed not informative variables and scaled quantitative ones. We considered recurrent genomic and cytogenetic lesions (present in ≥5 patients), platelets, hemoglobin and bone marrow blasts (%), age and sex as covariates. To explore the main patterns of expression changes, PCA was performed to reduce multidimensional correlated expression features (20 PCs was selected, explaining 42% of the total transcriptomic variability). To evaluate the prognostic power of each data layer we grouped all available features into five groups: gene mutations (n=15), cytogenetic alterations (n=7), expression data (n=20), blood counts (n=3) and demographic variables (n=2). Within a 5-fold CV we combined these variables in our integrative model to calculate MDS patients risk. The obtained predictive accuracy (C-index) for OS was 0.83, underlying that transcriptomic data significantly improved the current standard prognostic scoring systems. Accordingly, in our patient population, the C-index of the conventional IPSS-R score and the new IPSS-M were 0.68 and 0.76, respectively. A similar improvement by adding transcriptomic data was observed in prediction of the risk of AML evolution. Moreover, by analyzing the contribution of each feature category to the OS probability ( Figure 1), in term of explained variance, the relative impact of transcriptomic is 40%, with the remaining prognostic information distributed among genomic features (somatic gene mutations and cytogenetics lesions, 24%), demographics (20%) and clinical features (15%). An independent validation of these results on 202 patients is currently ongoing. Figure 2 shows an example of personalized survival prediction using patients from the study population. In two subjects with same clinical phenotype and mutations leading to a similar IPSS-M prognosis, the integrative model captures additional prognostic information and efficiently predicts clinical outcome. Given the complexity of our model, specific technological support is needed to combine data at individual patient level and to translate it into a personalized outcome prediction. To this aim, we created a prototype web portal based on our dataset for user-defined genomic/transcriptomic and clinical features. Conclusion. In predicting survival of MDS patients, genomic, transcriptomic and diagnostic clinical variables all have utility, with a significant contribution from the transcriptome.
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Sadeghi, Iman, Juan D. Gispert, Emilio Palumbo, Manuel Muñoz-Aguirre, Valentin Wucher, Valeria D'Argenio, Gabriel Santpere, Arcadi Navarro, Roderic Guigo, and Natàlia Vilor-Tejedor. "Brain transcriptomic profiling reveals common alterations across neurodegenerative and psychiatric disorders." Computational and Structural Biotechnology Journal 20 (2022): 4549–61. http://dx.doi.org/10.1016/j.csbj.2022.08.037.
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Tian, Zhaojun. "Ageing-Associated Transcriptomic Alterations in Peri-Implantitis Pathology: A Bioinformatic Study." Disease Markers 2022 (October 11, 2022): 1–21. http://dx.doi.org/10.1155/2022/8456968.
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Background. Ageing is associated with increased incidence of peri-implantitis but the roles of ageing-associated biological mechanisms in the occurrence of peri-implantitis are not known. This study is aimed at performing integrative bioinformatic analysis of publically available datasets to uncover molecular mechanisms related to ageing and peri-implantitis. Methods. Gene expression datasets related to ageing and peri-implantitis (PI) were sought, and differentially expressed genes (DEGs) were analysed. Ageing-related genes were also identified from the “Aging Atlas” database. Using intersection analysis, an age-related-PI gene set was identified. Functional enrichment analysis for enriched GO biological process and KEGG pathways, protein-protein interaction (PPI) network analysis, correlation analysis, and immune cell infiltration analysis to determine high-abundance immune cells were performed. Least absolute shrinkage and selection operator (LASSO) logistic regression identified key age-related-PI genes. Transcription factor-gene and drug-gene interactions and enriched KEGG pathways for the key age-related-PI genes were determined. Results. A total of 52 genes were identified as age-related-PI genes and found enriched in several inflammation-associated processes including myeloid leukocyte activation, acute inflammatory response, mononuclear cell differentiation, B cell activation, NF-kappa B signalling, IL-17 signalling, and TNF signalling. LYN, CDKN2A, MAPT, BTK, and PRKCB were hub genes in the PPI network. Immune cell infiltration analysis showed activated dendritic cells, central memory CD4 T cells, immature dendritic cells, and plasmacytoid dendritic cells were highly abundant in PI and ageing. 7 key age-related PI genes including ALOX5AP, EAF2, FAM46C, GZMK, MAPT, RGS1, and SOSTDC1 were identified using LASSO with high predictive values and found to be enriched in multiple neurodegeneration-associated pathways, MAPK signalling, and Fc epsilon RI signalling. MAPT and ALOX5AP were associated with multiple drugs and transcription factors and interacted with other age-related genes to regulate multiple biological pathways. Conclusion. A suite of bioinformatics analysis identified a 7-signature gene set highly relevant to cooccurrence of ageing and peri-implantitis and highlighted the role of neurodegeneration, autoimmune, and inflammation related pathways. MAPT and ALOX5AP were identified as key candidate target genes for clinical translation.
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Yang, Dan, Yong Zeng, Cui Tian, Jing Liu, Shu-Bin Guo, Yue-Hong Zheng, and Hui-Hua Li. "Transcriptomic Analysis of Mild Hypothermia-dependent Alterations During Endothelial Reperfusion Injury." Cellular Physiology and Biochemistry 25, no. 6 (2010): 605–14. http://dx.doi.org/10.1159/000315079.
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Zhang, Chao, Zhiqing Ma, Xing Zhang, and Hua Wu. "Transcriptomic alterations in Sitophilus zeamais in response to allyl isothiocyanate fumigation." Pesticide Biochemistry and Physiology 137 (April 2017): 62–70. http://dx.doi.org/10.1016/j.pestbp.2016.10.001.
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Lai, Keng-Po, Jing-Woei Li, Christine Ying-Shan Chan, Ting-Fung Chan, Karen Wing-Yee Yuen, and Jill Man-Ying Chiu. "Transcriptomic alterations in Daphnia magna embryos from mothers exposed to hypoxia." Aquatic Toxicology 177 (August 2016): 454–63. http://dx.doi.org/10.1016/j.aquatox.2016.06.020.
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Adashek, Jacob J., Shumei Kato, Rahul Parulkar, Christopher Szeto, Sandeep K. Reddy, and Razelle Kurzrock. "RNAseq in addition to next generation sequencing in advanced genitourinary cancers reveals transcriptomic silencing of DNA mutations: Implications for resistance to targeted therapeutics." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 583. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.583.
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583 Background: Next generation sequencing (NGS) for advanced tumors is becoming more routine. However, not all patients respond to precision matched treatments. We hypothesized that one potential reason for treatment failure with targeted therapy could be discrepancies between DNA alterations and RNA expression. Methods: Tumor samples from patients with metastatic kidney, bladder, and prostate cancer were analyzed by whole exome or whole genome NGS and RNA sequencing (CLIA-certified laboratory; NantOmics LLC, Santa Cruz, CA). Only known pathogenic driver alterations were analyzed in the current study. Results: Of 45 patients, 10 had kidney cancer, 18 had bladder cancer; and 17 had prostate cancer. Median age was 66 years (range, 28 - 86). The most commonly altered genes were TP53 (35.6% [16/45]), PIK3CA (15.6% [7/45]), FGFR3 (11.1% [5/45]), ALK (8.9% [4/45]), and ATM (8.9% [4/45]). In total, 86 pathogenic DNA alterations were identified; 17 of these (19.8%) were not observed at the RNA level. Among 45 patients, 31.1% (14/45) had ≥1 DNA alteration that was not expressed at the RNA level. Discordance between DNA and RNA was seen in 40% of patients with kidney cancer (4/10), 28% of patients with bladder cancer (5/18), and 29% with prostate cancer (5/17). Examples of genes that had pathogenic DNA alterations not seen at the RNA level included ALK (four discordant cases), KDR (three discordant cases) and GNAS (one discordant case). On the other hand, alterations involving certain genes showed 100% concordance between DNA and RNA: TP53 [N = 16], PIK3CA [N = 7], and FGFR3 [N = 5]). Conclusions: A significant number of patients with genitourinary tumors had DNA alterations that are silenced at the RNA level (19.8%). Transcriptomic silencing merits additional investigation as a mechanism that could mediate resistance to therapeutics targeted at cognate alterations.
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Seefelder, Manuel, and Stefan Kochanek. "A meta-analysis of transcriptomic profiles of Huntington’s disease patients." PLOS ONE 16, no. 6 (June 10, 2021): e0253037. http://dx.doi.org/10.1371/journal.pone.0253037.
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Description of robust transcriptomic alterations in Huntington’s disease is essential to identify targets for biochemical studies and drug development. We analysed publicly available transcriptome data from the brain and blood of 220 HD patients and 241 healthy controls and identified 737 and 661 genes with robustly altered mRNA levels in the brain and blood of HD patients, respectively. In the brain, a subnetwork of 320 genes strongly correlated with HD and was enriched in transport-related genes. Bioinformatical analysis of this subnetwork highlighted CDC42, PAK1, YWHAH, NFY, DLX1, HMGN3, and PRMT3. Moreover, we found that CREB1 can regulate 78.0% of genes whose mRNA levels correlated with HD in the blood of patients. Alterations in protein transport, metabolism, transcriptional regulation, and CDC42-mediated functions are likely central features of HD. Further our data substantiate the role of transcriptional regulators that have not been reported in the context of HD (e.g. DLX1, HMGN3 and PRMT3) and strongly suggest dysregulation of NFY and its target genes across tissues. A large proportion of the identified genes such as CDC42 were also altered in Parkinson’s (PD) and Alzheimer’s disease (AD). The observed dysregulation of CDC42 and YWHAH in samples from HD, AD and PD patients indicates that those genes and their upstream regulators may be interesting therapeutic targets.
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Magnin-Robert, Maryline, Marielle Adrian, Sophie Trouvelot, Alessandro Spagnolo, Lucile Jacquens, Patricia Letousey, Fanja Rabenoelina, et al. "Alterations in Grapevine Leaf Metabolism Occur Prior to Esca Apoplexy Appearance." Molecular Plant-Microbe Interactions® 30, no. 12 (December 2017): 946–59. http://dx.doi.org/10.1094/mpmi-02-17-0036-r.
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Esca disease is one of the major grapevine trunk diseases in Europe and the etiology is complex, since several inhabiting fungi are identified to be associated with this disease. Among the foliar symptom expressions, the apoplectic form may be distinguished and characterized by sudden dieback of shoots, leaf drop, and shriveling of grape clusters in a few days that can ultimately induce the plant death. To further understand this drastic event, we conducted transcriptomic and metabolomic analyses to characterize responses of leaves during the period preceding symptom appearance (20 and 7 days before foliar symptom expression) and at the day of apoplexy expression. Transcriptomic and metabolomic analyses provide signatures for the apoplectic leaves and most changes concerning the metabolism of carbohydrates, amino acids, and phenylpropanoids. In deciphering glutathione-S-transferase (GST), its preferential location in phloem, correlated with the upregulation of GST genes and a decrease of the glutathione level, offers further support to the putative role of glutathione during apoplexy expression.
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Yang, Yang, TingTing Feng, Xiaojun Fan, Xia Zhou, Wu'an Bao, Danhong Zhang, Hua Bao, et al. "Abstract 6054: Genomic and transcriptomic remodeling of esophageal squamous cell carcinoma by neo-adjuvant radiochemotherapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6054. http://dx.doi.org/10.1158/1538-7445.am2022-6054.
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Abstract Objective: To identify genetic and clinicopathological factors that affect the response of patients with esophageal squamous cell carcinoma (ESCC) to neoadjuvant chemoradiotherapy (nCRT), profile the genomic and transcriptomic alterations after nCRT and relate the alterations to patient’s prognosis. Methods: A total of 137 samples from 57 ESCC patients undergoing nCRT were collected. 82 samples including 54 pre-treatment samples and 28 post-treatment samples were subjected to whole-exome sequencing, and 55 samples including 26 pre-treatment samples and 29 post-treatment samples were subjected to RNA-seq analysis. Genetic and clinicopathological factors associated with patient’s response to nCRT were identified by comparing baseline features of patients achieving pathological response (pCR) and patients not achieving pCR. Genomic and transcriptomic profiles before and after nCRT were compared to identify features acquired during nCRT and the association of identified features with patient’s recurrence-free survival (RFS) and overall survival (OS) were investigated. Results: Co-deficiency of DDR and HIPPO pathway at baseline synergistically sensitized ESCC to nCRT. The arachidonic acid metabolism pathway was upregulated at baseline in patients with pCR. The proportion of small deletion and insertion (INDEL %) significantly increased in acquired mutations (p<0.001) and was positively correlated with focal chromosomal loss (Spearman's ρ=0.52, p=0.005) and negatively correlated with broad chromosomal gain (Spearman's ρ=-0.61, p<0.001) after nCRT. Acquired INDEL% was associated with tumor regression grade (TRG) (p=0.06) and predicted the worse RFS (p=0.16) and OS (p=0.067). The degree of clonal expansion during nCRT was associated with patient’s RFS (p=0.0087) and OS (p=0.023), and negative correlated with acquired INDEL % (Spearman's ρ=-0.45, p=0.02). The expression profile of tumor tissue was changed after nCRT and displayed upregulation of cell adhesion and stromal related pathways and downregulation of DNA replication and cell cycle pathways, and the alteration of expression profile was associated with patient’s prognosis. Conclusions: nCRT remodels the genome and transcriptome of ESCC. Small deletion/insertion and focal chromosomal loss may be characteristic genomic alterations imposed by radiation. Acquired INDEL proportion is a biomarker to indicate the efficacy of nCRT and predict patient’s prognosis. The degree of clonal expansion during nCRT reflects the treatment resistance and associated with patient’s prognosis. Citation Format: Yang Yang, TingTing Feng, Xiaojun Fan, Xia Zhou, Wu'an Bao, Danhong Zhang, Hua Bao, Junrong Yan, Xue Wu, Yang Shao, Guoqin Qiu, Dan Su, Qixun Chen. Genomic and transcriptomic remodeling of esophageal squamous cell carcinoma by neo-adjuvant radiochemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6054.