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1
Zappone, M. V., R. Galli, R. Catena, N. Meani, S. De Biasi, E. Mattei, C. Tiveron et al. « Sox2 regulatory sequences direct expression of a (beta)-geo transgene to telencephalic neural stem cells and precursors of the mouse embryo, revealing regionalization of gene expression in CNS stem cells ». Development 127, no 11 (1 juin 2000) : 2367–82. http://dx.doi.org/10.1242/dev.127.11.2367.
Texte intégralRésumé :
Sox2 is one of the earliest known transcription factors expressed in the developing neural tube. Although it is expressed throughout the early neuroepithelium, we show that its later expression must depend on the activity of more than one regionally restricted enhancer element. Thus, by using transgenic assays and by homologous recombination-mediated deletion, we identify a region upstream of Sox2 (−5.7 to −3.3 kb) which can not only drive expression of a (beta)-geo transgene to the developing dorsal telencephalon, but which is required to do so in the context of the endogenous gene. The critical enhancer can be further delimited to an 800 bp fragment of DNA surrounding a nuclease hypersensitive site within this region, as this is sufficient to confer telencephalic expression to a 3.3 kb fragment including the Sox2 promoter, which is otherwise inactive in the CNS. Expression of the 5.7 kb Sox2(beta)-geo transgene localizes to the neural plate and later to the telencephalic ventricular zone. We show, by in vitro clonogenic assays, that transgene-expressing (and thus G418-resistant) ventricular zone cells include cells displaying functional properties of stem cells, i.e. self-renewal and multipotentiality. We further show that the majority of telencephalic stem cells express the transgene, and this expression is largely maintained over two months in culture (more than 40 cell divisions) in the absence of G418 selective pressure. In contrast, stem cells grown in parallel from the spinal cord never express the transgene, and die in G418. Expression of endogenous telencephalic genes was similarly observed in long-term cultures derived from the dorsal telencephalon, but not in spinal cord-derived cultures. Thus, neural stem cells of the midgestation embryo are endowed with region-specific gene expression (at least with respect to some networks of transcription factors, such as that driving telencephalic expression of the Sox2 transgene), which can be inherited through multiple divisions outside the embryonic environment.
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Mariani, J., R. Favaro, C. Lancini, G. Vaccari, A. L. Ferri, J. Bertolini, D. Tonoli et al. « Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers ». Nucleic Acids Research 40, no 14 (10 avril 2012) : 6461–76. http://dx.doi.org/10.1093/nar/gks295.
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Wei, Chia-Lin, Silvia K. Nicolis, Yanfen Zhu et Miriam Pagin. « Sox2-Dependent 3D Chromatin Interactomes in Transcription, Neural Stem Cell Proliferation and Neurodevelopmental Diseases ». Journal of Experimental Neuroscience 13 (janvier 2019) : 117906951986822. http://dx.doi.org/10.1177/1179069519868224.
Texte intégralRésumé :
In our article, we asked whether Sox2, a transcription factor important in brain development and disease, is involved in gene regulation through its action on long-range interactions between promoters and distant enhancers. Our findings highlight that Sox2 shapes a genome-wide network of promoter-enhancer interactions, acting by direct binding to these elements. Sox2 loss affects the three-dimensional (3D) genome and decreases the activity of a subset of genes involved in Sox2-bound interactions. At least one of such downregulated genes, Socs3, is critical for long-term neural stem cell maintenance. These results point to the possibility of identifying a transcriptional network downstream to Sox2, and involved in neural stem cell maintenance. In addition, interacting Sox2-bound enhancers are often connected to genes which are relevant, in man, to neurodevelopmental disease; this may facilitate the detection of functionally relevant mutations in regulatory elements in man, contributing to neural disease.
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Bouzas, Santiago O., Melisa S. Marini, Eliana Torres Zelada, Ailín L. Buzzi, David A. Morales Vicente et Pablo H. Strobl-Mazzulla. « Epigenetic activation of Sox2 gene in the developing vertebrate neural plate ». Molecular Biology of the Cell 27, no 12 (15 juin 2016) : 1921–27. http://dx.doi.org/10.1091/mbc.e16-01-0042.
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One of the earliest manifestations of neural induction is onset of expression of the neural marker Sox2, mediated by the activation of the enhancers N1 and N2. By using loss and gain of function, we find that Sox2 expression requires the activity of JmjD2A and the Msk1 kinase, which can respectively demethylate the repressive H3K9me3 mark and phosphorylate the activating H3S10 (H3S10ph) mark. Bimolecular fluorescence complementation reveals that the adaptor protein 14-3-3, known to bind to H3S10ph, interacts with JMJD2A and may be involved in its recruitment to regulatory regions of the Sox2 gene. Chromatin immunoprecipitation reveals dynamic binding of JMJD2A to the Sox2 promoter and N-1 enhancer at the time of neural plate induction. Finally, we show a clear temporal antagonism on the occupancy of H3K9me3 and H3S10ph modifications at the promoter of the Sox2 locus before and after the neural plate induction. Taken together, our results propose a series of epigenetic events necessary for the early activation of the Sox2 gene in neural progenitor cells.
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Tsai, Ping-Hsing, Yueh Chien, Mong-Lien Wang, Chih-Hung Hsu, Benoit Laurent, Shih-Jie Chou, Wei-Chao Chang et al. « Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network ». Nucleic Acids Research 47, no 19 (26 septembre 2019) : 10115–33. http://dx.doi.org/10.1093/nar/gkz801.
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Abstract Pluripotency and cell fates can be modulated through the regulation of super-enhancers; however, the underlying mechanisms are unclear. Here, we showed a novel mechanism in which Ash2l directly binds to super-enhancers of several stemness genes to regulate pluripotency and self-renewal in pluripotent stem cells. Ash2l recruits Oct4/Sox2/Nanog (OSN) to form Ash2l/OSN complex at the super-enhancers of Jarid2, Nanog, Sox2 and Oct4, and further drives enhancer activation, upregulation of stemness genes, and maintains the pluripotent circuitry. Ash2l knockdown abrogates the OSN recruitment to all super-enhancers and further hinders the enhancer activation. In addition, CRISPRi/dCas9-mediated blocking of Ash2l-binding motifs at these super-enhancers also prevents OSN recruitment and enhancer activation, validating that Ash2l directly binds to super-enhancers and initiates the pluripotency network. Transfection of Ash2l with W118A mutation to disrupt Ash2l–Oct4 interaction fails to rescue Ash2l-driven enhancer activation and pluripotent gene upregulation in Ash2l-depleted pluripotent stem cells. Together, our data demonstrated Ash2l formed an enhancer-bound Ash2l/OSN complex that can drive enhancer activation, govern pluripotency network and stemness circuitry.
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Niu, Cong, Siqing Wang, Jieyu Guo, Xiangxiang Wei, Mengping Jia, Zhaoxiong Chen, Wenxuan Gong et al. « BACH1 recruits NANOG and histone H3 lysine 4 methyltransferase MLL/SET1 complexes to regulate enhancer–promoter activity and maintains pluripotency ». Nucleic Acids Research 49, no 4 (27 janvier 2021) : 1972–86. http://dx.doi.org/10.1093/nar/gkab034.
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Abstract Maintenance of stem-cell identity requires proper regulation of enhancer activity. Both transcription factors OCT4/SOX2/NANOG and histone methyltransferase complexes MLL/SET1 were shown to regulate enhancer activity, but how they are regulated in embryonic stem cells (ESCs) remains further studies. Here, we report a transcription factor BACH1, which directly interacts with OCT4/SOX2/NANOG (OSN) and MLL/SET1 methyltransferase complexes and maintains pluripotency in mouse ESCs (mESCs). BTB domain and bZIP domain of BACH1 are required for these interactions and pluripotency maintenance. Loss of BACH1 reduced the interaction between NANOG and MLL1/SET1 complexes, and decreased their occupancy on chromatin, and further decreased H3 lysine 4 trimethylation (H3K4me3) level on gene promoters and (super-) enhancers, leading to decreased enhancer activity and transcription activity, especially on stemness-related genes. Moreover, BACH1 recruited NANOG through chromatin looping and regulated remote NANOG binding, fine-tuning enhancer–promoter activity and gene expression. Collectively, these observations suggest that BACH1 maintains pluripotency in ESCs by recruiting NANOG and MLL/SET1 complexes to chromatin and maintaining the trimethylated state of H3K4 and enhancer–promoter activity, especially on stemness-related genes.
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Aguirre-Vázquez, Alain, Luis A. Salazar-Olivo, Xóchitl Flores-Ponce, Ana L. Arriaga-Guerrero, Dariela Garza-Rodríguez, María E. Camacho-Moll, Iván Velasco, Fabiola Castorena-Torres, Nidheesh Dadheech et Mario Bermúdez de León. « 5-Aza-2′-Deoxycytidine and Valproic Acid in Combination with CHIR99021 and A83-01 Induce Pluripotency Genes Expression in Human Adult Somatic Cells ». Molecules 26, no 7 (29 mars 2021) : 1909. http://dx.doi.org/10.3390/molecules26071909.
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A generation of induced pluripotent stem cells (iPSC) by ectopic expression of OCT4, SOX2, KLF4, and c-MYC has established promising opportunities for stem cell research, drug discovery, and disease modeling. While this forced genetic expression represents an advantage, there will always be an issue with genomic instability and transient pluripotency genes reactivation that might preclude their clinical application. During the reprogramming process, a somatic cell must undergo several epigenetic modifications to induce groups of genes capable of reactivating the endogenous pluripotency core. Here, looking to increase the reprograming efficiency in somatic cells, we evaluated the effect of epigenetic molecules 5-aza-2′-deoxycytidine (5AZ) and valproic acid (VPA) and two small molecules reported as reprogramming enhancers, CHIR99021 and A83-01, on the expression of pluripotency genes and the methylation profile of the OCT4 promoter in a human dermal fibroblasts cell strain. The addition of this cocktail to culture medium increased the expression of OCT4, SOX2, and KLF4 expression by 2.1-fold, 8.5-fold, and 2-fold, respectively, with respect to controls; concomitantly, a reduction in methylated CpG sites in OCT4 promoter region was observed. The epigenetic cocktail also induced the expression of the metastasis-associated gene S100A4. However, the epigenetic cocktail did not induce the morphological changes characteristic of the reprogramming process. In summary, 5AZ, VPA, CHIR99021, and A83-01 induced the expression of OCT4 and SOX2, two critical genes for iPSC. Future studies will allow us to precise the mechanisms by which these compounds exert their reprogramming effects.
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Wang, Bin, Jing Sun, Jiandong Shi, Qing Guo, Xiangrong Tong, Jin Zhang, Ningzhu Hu et YunZhang Hu. « Small-Activating RNA Can Change Nucleosome Positioning in Human Fibroblasts ». Journal of Biomolecular Screening 21, no 6 (18 mars 2016) : 634–42. http://dx.doi.org/10.1177/1087057116637562.
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RNA activation (RNAa) is a mechanism of positive gene expression regulation mediated by small-activating RNAs (saRNAs), which target gene promoters and have been used as tools to manipulate gene expression. Studies have shown that RNAa is associated with epigenetic modifications at promoter regions; however, it is unclear whether these modifications are the cause or a consequence of RNAa. In this study, we examined changes in nucleosome repositioning and the involvement of RNA polymerase II (RNAPII) in this process. We screened saRNAs for OCT4 ( POU5F1), SOX2, and NANOG, and identified several novel saRNAs. We found that nucleosome positioning was altered after saRNA treatment and that the formation of nucleosome-depleted regions (NDRs) contributed to RNAa at sites of RNAPII binding, such as the TATA box, CpG islands (CGIs), proximal enhancers, and proximal promoters. Moreover, RNAPII appeared to be bound specifically to NDRs. These results suggested that changes in nucleosome positions resulted from RNAa. We thus propose a hypothesis that targeting promoter regions using exogenous saRNAs can induce the formation of NDRs, exposing regulatory binding sites to recruit RNAPII, a key component of preinitiation complex, and leading to increased initiation of transcription.
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Huang, Tina, Juan Wang, Ye Hou, Andrea Piunti, Elizabeth Bartom, Ali Shilatifard, Feng Yue et Amanda Saratsis. « HGG-01. 3D GENOME STRUCTURE IMPACTS GENE EXPRESSION IN PEDIATRIC HIGH-GRADE GLIOMA ». Neuro-Oncology 23, Supplement_1 (1 juin 2021) : i17. http://dx.doi.org/10.1093/neuonc/noab090.067.
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Abstract Introduction Pediatric high-grade gliomas (pHGGs), including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), are highly morbid brain tumors. Up to 80% of DIPGs harbor a somatic missense mutation in genes encoding Histone H3. To investigate whether the H3K27M mutant protein is associated with distinct chromatin structure affecting transcription regulation, we generated the first high-resolution Hi-C and ATAC-Seq maps of pHGG cell lines, and integrated these with tissue and cell genomic data. Methods We generated sequencing data from patient-derived cell lines (DIPG n=6, GBM n=3, normal n=2) and frozen tissue specimens (DIPG n=1, normal brainstem n=1). Analyses included cell line RNA-Seq, ChIP-Seq (H3K27ac, H3K27me3, H3K27M) and genome-wide chromatin conformation capture (Hi-C), as well as tissue ATAC-Seq. Publicly available pediatric glioma tissue ChIP-Seq data was integrated with cell data. Results We identified tumor-specific enhancers and regulatory networks for known oncogenes in DIPG and GBM. In DIPG, FOX, SOX, STAT and SMAD families were among top H3K27Ac enriched motifs. Significant differences in Topologically Associating Domains (TADs) and DNA looping were observed at OLIG2 and MYCN in H3K27M mutant DIPG, relative to wild-type GBM and normal cells. Pharmacologic treatment targeting H3K27Ac (BET and Bromodomain inhibition) altered these 3D structures. Functional analysis of differentially enriched enhancers in DIPG implicated SOX2, SUZ12, and TRIM24 as top activated upstream regulators. Distinct genomic structural variations leading to enhancer hijacking and gene co-amplification were identified at A2M, JAG2, and FLRT1. Conclusion We show genome structural variations enhancer-promoter interactions that impact gene expression in pHGG in the presence and absence of the H3K27M mutation. Our results imply that tridimensional genome alterations may play a critical role in the pHGG epigenetic landscape and thereby contribute to pediatric gliomagenesis. Further studies examining the impact of the alterations, including CRISPR knock-down of target enhancer regions, is therefore underway.
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Huang, Tina, Juan Wang, Ye Hu, Andrea Piunti, Elizabeth Bartom, Ali Shilatifard, Feng Yue et Amanda Saratsis. « HGG-02. Epigenetic transcription regulation and 3D genome structure in pediatric high-grade glioma ». Neuro-Oncology 24, Supplement_1 (1 juin 2022) : i59—i60. http://dx.doi.org/10.1093/neuonc/noac079.218.
Texte intégralRésumé :
Abstract INTRODUCTION: Pediatric high-grade gliomas (pHGGs), including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), are highly morbid brain tumors. Up to 80% of DIPGs harbor a somatic missense mutation in genes encoding Histone H3. To investigate whether the H3K27M mutant protein is associated with distinct chromatin structure affecting transcription regulation, we generated the first high-resolution Hi-C and ATAC-Seq maps of pHGG cell lines, and integrated these with tissue and cell genomic data. METHODS: We generated sequencing data from patient-derived cell lines (DIPG n=6, GBM n=3, normal n=2) and frozen tissue specimens (DIPG n=1, normal brainstem n=1). Analyses included cell line RNA-Seq, ChIP-Seq (H3K27ac, H3K27me3, H3K27M) and genome-wide chromatin conformation capture (Hi-C), as well as tissue ATAC-Seq. Publicly available pediatric glioma tissue ChIP-Seq data was integrated with cell data. CRISPR knock-down of target enhancer regions was performed. RESULTS: We identified tumor-specific enhancers and regulatory networks for known oncogenes in DIPG and GBM. In DIPG, FOX, SOX, STAT and SMAD families were among top H3K27Ac enriched motifs. Significant differences in Topologically Associating Domains (TADs) and DNA looping were observed at OLIG2 and MYCN in H3K27M mutant DIPG, relative to wild-type GBM and normal cells. Pharmacologic treatment targeting H3K27Ac (BET and Bromodomain inhibition) altered these 3D structures. Functional analysis of differentially enriched enhancers in DIPG implicated SOX2, SUZ12, and TRIM24 as top activated upstream regulators. Distinct genomic structural variations leading to enhancer hijacking and gene co-amplification were identified at A2M, JAG2, and FLRT1. CONCLUSION: We show genome structural variations enhancer-promoter interactions that impact gene expression in pHGG in the presence and absence of the H3K27M mutation. Our results imply that tridimensional genome alterations may play a critical role in the pHGG epigenetic landscape and thereby contribute to pediatric gliomagenesis. Further studies examining the impact of the alterations are therefore underway.
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Huang, Tina, Juan Wang, Ye Hu, Andrea Piunti, Elizabeth Bartom, Ali Shilatifard, Feng Yue et Amanda Saratsis. « EPCO-20. PEDIATRIC HIGH-GRADE GLIOMA EXHIBITS DISTINCT 3D GENOME STRUCTURE THAT IMPACTS TRANSCRIPTION REGULATION ». Neuro-Oncology 23, Supplement_6 (2 novembre 2021) : vi6. http://dx.doi.org/10.1093/neuonc/noab196.019.
Texte intégralRésumé :
Abstract INTRODUCTION Pediatric high-grade gliomas (pHGGs), including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), are highly morbid brain tumors. Up to 80% of DIPGs harbor a somatic missense mutation in genes encoding Histone H3. To investigate whether the H3K27M mutant protein is associated with distinct chromatin structure affecting transcription regulation, we generated the first high-resolution Hi-C and ATAC-Seq maps of pHGG cell lines, and integrated these with tissue and cell genomic data. METHODS We generated sequencing data from patient-derived cell lines (DIPG n=6, GBM n=3, normal n=2) and frozen tissue specimens (DIPG n=1, normal brainstem n=1). Analyses included cell line RNA-Seq, ChIP-Seq (H3K27ac, H3K27me3, H3K27M) and genome-wide chromatin conformation capture (Hi-C), as well as tissue ATAC-Seq. Publicly available pediatric glioma tissue ChIP-Seq data was integrated with cell data. CRISPR knock-down of target enhancer regions was performed. RESULTS We identified tumor-specific enhancers and regulatory networks for known oncogenes in DIPG and GBM. In DIPG, FOX, SOX, STAT and SMAD families were among top H3K27Ac enriched motifs. Significant differences in Topologically Associating Domains (TADs) and DNA looping were observed at OLIG2 and MYCN in H3K27M mutant DIPG, relative to wild-type GBM and normal cells. Pharmacologic treatment targeting H3K27Ac (BET and Bromodomain inhibition) altered these 3D structures. Functional analysis of differentially enriched enhancers in DIPG implicated SOX2, SUZ12, and TRIM24 as top activated upstream regulators. Distinct genomic structural variations leading to enhancer hijacking and gene co-amplification were identified at A2M, JAG2, and FLRT1. CONCLUSION We show genome structural variations enhancer-promoter interactions that impact gene expression in pHGG in the presence and absence of the H3K27M mutation. Our results imply that tridimensional genome alterations may play a critical role in the pHGG epigenetic landscape and thereby contribute to pediatric gliomagenesis. Further studies examining the impact of the alterations is therefore underway.
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Markov, Glenn J., Thach Mai, Surag Nair, Anna Shcherbina, Yu Xin Wang, David M. Burns, Anshul Kundaje et Helen M. Blau. « AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency ». Proceedings of the National Academy of Sciences 118, no 23 (4 juin 2021) : e2104841118. http://dx.doi.org/10.1073/pnas.2104841118.
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Somatic cell transcription factors are critical to maintaining cellular identity and constitute a barrier to human somatic cell reprogramming; yet a comprehensive understanding of the mechanism of action is lacking. To gain insight, we examined epigenome remodeling at the onset of human nuclear reprogramming by profiling human fibroblasts after fusion with murine embryonic stem cells (ESCs). By assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and chromatin immunoprecipitation sequencing we identified enrichment for the activator protein 1 (AP-1) transcription factor c-Jun at regions of early transient accessibility at fibroblast-specific enhancers. Expression of a dominant negative AP-1 mutant (dnAP-1) reduced accessibility and expression of fibroblast genes, overcoming the barrier to reprogramming. Remarkably, efficient reprogramming of human fibroblasts to induced pluripotent stem cells was achieved by transduction with vectors expressing SOX2, KLF4, and inducible dnAP-1, demonstrating that dnAP-1 can substitute for exogenous human OCT4. Mechanistically, we show that the AP-1 component c-Jun has two unexpected temporally distinct functions in human reprogramming: 1) to potentiate fibroblast enhancer accessibility and fibroblast-specific gene expression, and 2) to bind to and repress OCT4 as a complex with MBD3. Our findings highlight AP-1 as a previously unrecognized potent dual gatekeeper of the somatic cell state.
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Renatino-Canevarolo, Rafael, Mark B. Meads, Maria Silva, Praneeth Reddy Sudalagunta, Christopher Cubitt, Gabriel De Avila, Raghunandan R. Alugubelli et al. « Dynamic Epigenetic Landscapes Define Multiple Myeloma Progression and Drug Resistance ». Blood 136, Supplement 1 (5 novembre 2020) : 32–33. http://dx.doi.org/10.1182/blood-2020-142872.
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Multiple myeloma (MM) is an incurable cancer of bone marrow-resident plasma cells, which evolves from a premalignant state, MGUS, to a form of active disease characterized by an initial response to therapy, followed by cycles of therapeutic successes and failures, culminating in a fatal multi-drug resistant cancer. The molecular mechanisms leading to disease progression and refractory disease in MM remain poorly understood. To address this question, we have generated a new database, consisting of 1,123 MM biopsies from patients treated at the H. Lee Moffitt Cancer Center. These samples ranged from MGUS to late relapsed/refractory (LR) disease, and were comprehensively characterized genetically (844 RNAseq, 870 WES, 7 scRNAseq), epigenetically (10 single-cell chromatin accessibility, scATAC-seq) and phenotypically (537 samples assessed for ex vivo drug resistance). Mutational analysis identified putative driver genes (e.g. NRAS, KRAS) among the highest frequent mutations, as well as a steady increase in mutational load across progression from MGUS to LR samples. However, with the exception of KRAS, these genes did not reach statistical significance according to FISHER's exact test between different disease stages, suggesting that no single mutation is necessary or sufficient to drive MM progression or refractory disease, but rather a common "driver" biology is critical. Pathway analysis of differentially expressed genes identified cell adhesion, inflammatory cytokines and hematopoietic cell identify as under-expressed in active MM vs. MGUS, while cell cycle, metabolism, DNA repair, protein/RNA synthesis and degradation were over-expressed in LR. Using an unsupervised systems biology approach, we reconstructed a gene expression map to identify transcriptomic reprogramming events associated with disease progression and evolution of drug resistance. At an epigenetic regulatory level, these genes were enriched for histone modifications (e.g. H3k27me3 and H3k27ac). Furthermore, scATAC-seq confirmed genome-wide alterations in chromatin accessibility across MM progression, involving shifts in chromatin accessibility of the binding motifs of epigenetic regulator complexes, known to mediate formation of 3D structures (CTCF/YY1) of super enhancers (SE) and cell identity reprograming (POU5F1/SOX2). Additionally, we have identified SE-regulated genes under- (EBF1, RB1, SPI1, KLF6) and over-expressed (PRDM1, IRF4) in MM progression, as well as over-expressed in LR (RFX5, YY1, NBN, CTCF, BCOR). We have found a correlation between cytogenetic abnormalities and mutations with differential gene expression observed in MM progression, suggesting groups of genetic events with equivalent transcriptomic effect: e.g. NRAS, KRAS, DIS3 and del13q are associated with transcriptomic changes observed during MGUS/SMOL=>active MM transition (Figure 1). Taken together, our preliminary data suggests that multiple independent combinations of genetic and epigenetic events (e.g. mutations, cytogenetics, SE dysregulation) alter the balance of master epigenetic regulatory circuitry, leading to genome-wide transcriptional reprogramming, facilitating disease progression and emergence of drug resistance. Figure 1: Topology of transcriptional regulation in MM depicts 16,738 genes whose expression is increased (red) or decreased (green) in presence of genetic abnormality. Differential expression associated with (A) hotspot mutations and (B) cytogenetic abnormalities confirms equivalence of expected pairs (e.g. NRAS and KRAS, BRAF and RAF1), but also proposes novel transcriptomic dysregulation effect of clinically relevant cytogenetic abnormalities, with yet uncharacterized molecular role in MM. Figure 1 Disclosures Kulkarni: M2GEN: Current Employment. Zhang:M2GEN: Current Employment. Hampton:M2GEN: Current Employment. Shain:GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; AbbVie: Research Funding; Takeda: Honoraria, Speakers Bureau; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive: Consultancy, Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Siqueira Silva:AbbVie: Research Funding; Karyopharm: Research Funding; NIH/NCI: Research Funding.
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Alexander, Jeffrey M., Juan Guan, Bingkun Li, Lenka Maliskova, Michael Song, Yin Shen, Bo Huang, Stavros Lomvardas et Orion D. Weiner. « Live-cell imaging reveals enhancer-dependent Sox2 transcription in the absence of enhancer proximity ». eLife 8 (24 mai 2019). http://dx.doi.org/10.7554/elife.41769.
Texte intégralRésumé :
Enhancers are important regulatory elements that can control gene activity across vast genetic distances. However, the underlying nature of this regulation remains obscured because it has been difficult to observe in living cells. Here, we visualize the spatial organization and transcriptional output of the key pluripotency regulator Sox2 and its essential enhancer Sox2 Control Region (SCR) in living embryonic stem cells (ESCs). We find that Sox2 and SCR show no evidence of enhanced spatial proximity and that spatial dynamics of this pair is limited over tens of minutes. Sox2 transcription occurs in short, intermittent bursts in ESCs and, intriguingly, we find this activity demonstrates no association with enhancer proximity, suggesting that direct enhancer-promoter contacts do not drive contemporaneous Sox2 transcription. Our study establishes a framework for interrogation of enhancer function in living cells and supports an unexpected mechanism for enhancer control of Sox2 expression that uncouples transcription from enhancer proximity.
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Fong, Yick W., Jaclyn J. Ho, Carla Inouye et Robert Tjian. « The dyskerin ribonucleoprotein complex as an OCT4/SOX2 coactivator in embryonic stem cells ». eLife 3 (19 novembre 2014). http://dx.doi.org/10.7554/elife.03573.
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Acquisition of pluripotency is driven largely at the transcriptional level by activators OCT4, SOX2, and NANOG that must in turn cooperate with diverse coactivators to execute stem cell-specific gene expression programs. Using a biochemically defined in vitro transcription system that mediates OCT4/SOX2 and coactivator-dependent transcription of the Nanog gene, we report the purification and identification of the dyskerin (DKC1) ribonucleoprotein complex as an OCT4/SOX2 coactivator whose activity appears to be modulated by a subset of associated small nucleolar RNAs (snoRNAs). The DKC1 complex occupies enhancers and regulates the expression of key pluripotency genes critical for self-renewal in embryonic stem (ES) cells. Depletion of DKC1 in fibroblasts significantly decreased the efficiency of induced pluripotent stem (iPS) cell generation. This study thus reveals an unanticipated transcriptional role of the DKC1 complex in stem cell maintenance and somatic cell reprogramming.
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Liu, Zhe, Wesley R. Legant, Bi-Chang Chen, Li Li, Jonathan B. Grimm, Luke D. Lavis, Eric Betzig et Robert Tjian. « 3D imaging of Sox2 enhancer clusters in embryonic stem cells ». eLife 3 (24 décembre 2014). http://dx.doi.org/10.7554/elife.04236.
Texte intégralRésumé :
Combinatorial cis-regulatory networks encoded in animal genomes represent the foundational gene expression mechanism for directing cell-fate commitment and maintenance of cell identity by transcription factors (TFs). However, the 3D spatial organization of cis-elements and how such sub-nuclear structures influence TF activity remain poorly understood. Here, we combine lattice light-sheet imaging, single-molecule tracking, numerical simulations, and ChIP-exo mapping to localize and functionally probe Sox2 enhancer-organization in living embryonic stem cells. Sox2 enhancers form 3D-clusters that are segregated from heterochromatin but overlap with a subset of Pol II enriched regions. Sox2 searches for specific binding targets via a 3D-diffusion dominant mode when shuttling long-distances between clusters while chromatin-bound states predominate within individual clusters. Thus, enhancer clustering may reduce global search efficiency but enables rapid local fine-tuning of TF search parameters. Our results suggest an integrated model linking cis-element 3D spatial distribution to local-versus-global target search modalities essential for regulating eukaryotic gene transcription.
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Chovanec, Peter, Amanda J. Collier, Christel Krueger, Csilla Várnai, Claudia I. Semprich, Stefan Schoenfelder, Anne E. Corcoran et Peter J. Rugg-Gunn. « Widespread reorganisation of pluripotent factor binding and gene regulatory interactions between human pluripotent states ». Nature Communications 12, no 1 (7 avril 2021). http://dx.doi.org/10.1038/s41467-021-22201-4.
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AbstractThe transition from naive to primed pluripotency is accompanied by an extensive reorganisation of transcriptional and epigenetic programmes. However, the role of transcriptional enhancers and three-dimensional chromatin organisation in coordinating these developmental programmes remains incompletely understood. Here, we generate a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells, and develop a network-graph approach to examine the atlas at multiple spatial scales. We uncover highly connected promoter hubs that change substantially in interaction frequency and in transcriptional co-regulation between pluripotent states. Small hubs frequently merge to form larger networks in primed cells, often linked by newly-formed Polycomb-associated interactions. We identify widespread state-specific differences in enhancer activity and interactivity that correspond with an extensive reconfiguration of OCT4, SOX2 and NANOG binding and target gene expression. These findings provide multilayered insights into the chromatin-based gene regulatory control of human pluripotent states.
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Zhang, Juqing, Yaqi Zhou, Wei Yue, Zhenshuo Zhu, Xiaolong Wu, Shuai Yu, Qiaoyan Shen et al. « Super-enhancers conserved within placental mammals maintain stem cell pluripotency ». Proceedings of the National Academy of Sciences 119, no 40 (26 septembre 2022). http://dx.doi.org/10.1073/pnas.2204716119.
Texte intégralRésumé :
Despite pluripotent stem cells sharing key transcription factors, their maintenance involves distinct genetic inputs. Emerging evidence suggests that super-enhancers (SEs) can function as master regulatory hubs to control cell identity and pluripotency in humans and mice. However, whether pluripotency-associated SEs share an evolutionary origin in mammals remains elusive. Here, we performed comprehensive comparative epigenomic and transcription factor binding analyses among pigs, humans, and mice to identify pluripotency-associated SEs. Like typical enhancers, SEs displayed rapid evolution in mammals. We showed that BRD4 is an essential and conserved activator for mammalian pluripotency-associated SEs. Comparative motif enrichment analysis revealed 30 shared transcription factor binding motifs among the three species. The majority of transcriptional factors that bind to identified motifs are known regulators associated with pluripotency. Further, we discovered three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) that displayed remarkable conservation in placental mammals and were sufficient to drive reporter gene expression in a pluripotency-dependent manner. Disruption of these conserved SEs through the CRISPR-Cas9 approach severely impaired stem cell pluripotency. Our study provides insights into the understanding of conserved regulatory mechanisms underlying the maintenance of pluripotency as well as species-specific modulation of the pluripotency-associated regulatory networks in mammals.
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Huang, Yinghua, Hui Zhang, Lulu Wang, Chuanqing Tang, Xiaogan Qin, Xinyu Wu, Meifang Pan et al. « JMJD3 acts in tandem with KLF4 to facilitate reprogramming to pluripotency ». Nature Communications 11, no 1 (8 octobre 2020). http://dx.doi.org/10.1038/s41467-020-18900-z.
Texte intégralRésumé :
Abstract The interplay between the Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and transcriptional/epigenetic co-regulators in somatic cell reprogramming is incompletely understood. Here, we demonstrate that the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3 plays conflicting roles in mouse reprogramming. On one side, JMJD3 induces the pro-senescence factor Ink4a and degrades the pluripotency regulator PHF20 in a reprogramming factor-independent manner. On the other side, JMJD3 is specifically recruited by KLF4 to reduce H3K27me3 at both enhancers and promoters of epithelial and pluripotency genes. JMJD3 also promotes enhancer-promoter looping through the cohesin loading factor NIPBL and ultimately transcriptional elongation. This competition of forces can be shifted towards improved reprogramming by using early passage fibroblasts or boosting JMJD3’s catalytic activity with vitamin C. Our work, thus, establishes a multifaceted role for JMJD3, placing it as a key partner of KLF4 and a scaffold that assists chromatin interactions and activates gene transcription.
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Chang, William, Yilin Zhao, Danielle Rayêe, Qing Xie, Masako Suzuki, Deyou Zheng et Ales Cvekl. « Dynamic changes in whole genome DNA methylation, chromatin and gene expression during mouse lens differentiation ». Epigenetics & ; Chromatin 16, no 1 (25 janvier 2023). http://dx.doi.org/10.1186/s13072-023-00478-7.
Texte intégralRésumé :
Abstract Background Cellular differentiation is marked by temporally and spatially coordinated gene expression regulated at multiple levels. DNA methylation represents a universal mechanism to control chromatin organization and its accessibility. Cytosine methylation of CpG dinucleotides regulates binding of methylation-sensitive DNA-binding transcription factors within regulatory regions of transcription, including promoters and distal enhancers. Ocular lens differentiation represents an advantageous model system to examine these processes as lens comprises only two cell types, the proliferating lens epithelium and postmitotic lens fiber cells all originating from the epithelium. Results Using whole genome bisulfite sequencing (WGBS) and microdissected lenses, we investigated dynamics of DNA methylation and chromatin changes during mouse lens fiber and epithelium differentiation between embryos (E14.5) and newborns (P0.5). Histone H3.3 variant chromatin landscapes were also generated for both P0.5 lens epithelium and fibers by chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq). Tissue-specific features of DNA methylation patterns are demonstrated via comparative studies with embryonic stem (ES) cells and neural progenitor cells (NPCs) at Nanog, Pou5f1, Sox2, Pax6 and Six3 loci. Comparisons with ATAC-seq and RNA-seq data demonstrate that reduced methylation is associated with increased expression of fiber cell abundant genes, including crystallins, intermediate filament (Bfsp1 and Bfsp2) and gap junction proteins (Gja3 and Gja8), marked by high levels of histone H3.3 within their transcribed regions. Interestingly, Pax6-binding sites exhibited predominantly DNA hypomethylation in lens chromatin. In vitro binding of Pax6 proteins showed Pax6’s ability to interact with sites containing one or two methylated CpG dinucleotides. Conclusions Our study has generated the first data on methylation changes between two different stages of mammalian lens development and linked these data with chromatin accessibility maps, presence of histone H3.3 and gene expression. Reduced DNA methylation correlates with expression of important genes involved in lens morphogenesis and lens fiber cell differentiation.
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Ruiz Ramírez, Andrea Virginia, et Ernesto Prado Montes de Oca. « Therapeutic Potential of Long Non-Coding RNAs of HIV-1, SARS-CoV-2, and Endogenous Retroviruses ». Frontiers in Virology 2 (29 avril 2022). http://dx.doi.org/10.3389/fviro.2022.849349.
Texte intégralRésumé :
Long non-protein coding RNAs (lncRNAs, predicted to be up to 200,000 in the human genome) are nucleic acids of more than 200 nucleotides that not only play primordial roles in the regulation of chromatin states, but also are capable of decoying or scaffolding proteins (e.g., transcription factors, TFs; host and viral proteins), DNA (e.g., promoters and enhancers), and RNA (e.g., miRNAs and hnRNAs) in 3D conformations acting in a chaperonin-like fashion. Specifically, lncRNAs modulate gene expression during the regulatory layers of transcription, RNA processing (splicing and indirectly editing), translation, and post-translational modifications including phosphorylation, acetylation, and ubiquitination. Accumulated evidence indicates that lncRNAs regulate antiviral immune responses mainly by transcription of IFN regulatory factors 1 (IRF1) and 4 (IRF4), which contribute to type I interferon (IFNα and IFNβ) upregulation. Some of the most common TFs regulated by lncRNAs are TP53, CTCF, MYC, SOX2, EZH2 SFPQ, SUZ12, STAT1, STAT3, and NF-kappa B. In this review, the known functions of selected lncRNAs genes in HIV/AIDS (MALAT1, HEAL, NRON, TAR-gag, TP53COR1/lincRNA-p21, NEAT1, NKILA, LINC01426 [formerly Uc002yug.2], FAS-AS1, LINC00173 [formerly FLJ42957/NCRNA00173], GAS5, and HIV-encoded antisense lncRNA) and COVID-19 (EGOT, MALAT1, NEAT1, DANCR, HOTAIR, FENDRR, LINC1505, FALCOR, and HISLA) are discussed. Furthermore, MALAT1 is also involved in subsequent complications such as deep vein thrombosis (DVT) in COVID-19. In addition, after the increased understanding of the role of lncRNAs from Human Endogenous Retroviruses (HERVs, predicted to be at least 582 different with 725,763 repeats of them in the human genome) in cancer (TROJAN) and heart development (BANCR), transcripts of HERVs as lnc-EPAV and lnc-ALVA1-AS1 have recently drawn attention as host protective agents against viral infections. A deeper knowledge of host and viral lncRNAs interactions and their regulation will pave the way for the design of novel drugs inspired by host- and viral-encoded lncRNAs. These novel drugs have the potential to reduce the burden of HIV/AIDS and COVID-19 twofold: (1) by increasing their efficacy and (2) by minimizing the side effects of current drugs. We expect that lncRNA drugs will be able to modulate human and viral transcription in an unprecedented way but still effectively maintain homeostasis by deploying functionality below the pathogenic threshold.