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Syding, Linn Amanda, Petr Nickl, Petr Kasparek et Radislav Sedlacek. « CRISPR/Cas9 Epigenome Editing Potential for Rare Imprinting Diseases : A Review ». Cells 9, no 4 (16 avril 2020) : 993. http://dx.doi.org/10.3390/cells9040993.
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Imprinting diseases (IDs) are rare congenital disorders caused by aberrant dosages of imprinted genes. Rare IDs are comprised by a group of several distinct disorders that share a great deal of homology in terms of genetic etiologies and symptoms. Disruption of genetic or epigenetic mechanisms can cause issues with regulating the expression of imprinted genes, thus leading to disease. Genetic mutations affect the imprinted genes, duplications, deletions, and uniparental disomy (UPD) are reoccurring phenomena causing imprinting diseases. Epigenetic alterations on methylation marks in imprinting control centers (ICRs) also alters the expression patterns and the majority of patients with rare IDs carries intact but either silenced or overexpressed imprinted genes. Canonical CRISPR/Cas9 editing relying on double-stranded DNA break repair has little to offer in terms of therapeutics for rare IDs. Instead CRISPR/Cas9 can be used in a more sophisticated way by targeting the epigenome. Catalytically dead Cas9 (dCas9) tethered with effector enzymes such as DNA de- and methyltransferases and histone code editors in addition to systems such as CRISPRa and CRISPRi have been shown to have high epigenome editing efficiency in eukaryotic cells. This new era of CRISPR epigenome editors could arguably be a game-changer for curing and treating rare IDs by refined activation and silencing of disturbed imprinted gene expression. This review describes major CRISPR-based epigenome editors and points out their potential use in research and therapy of rare imprinting diseases.
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Nakamura, Muneaki, Alexis E. Ivec, Yuchen Gao et Lei S. Qi. « Durable CRISPR-Based Epigenetic Silencing ». BioDesign Research 2021 (1 juillet 2021) : 1–8. http://dx.doi.org/10.34133/2021/9815820.
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Development of CRISPR-based epigenome editing tools is important for the study and engineering of biological behavior. Here, we describe the design of a reporter system for quantifying the ability of CRISPR epigenome editors to produce a stable gene repression. We characterize the dynamics of durable gene silencing and reactivation, as well as the induced epigenetic changes of this system. We report the creation of single-protein CRISPR constructs bearing combinations of three epigenetic editing domains, termed KAL, that can stably repress the gene expression. This system should allow for the development of novel epigenome editing tools which will be useful in a wide array of biological research and engineering applications.
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Fang, Yongxing, Wladislaw Stroukov, Toni Cathomen et Claudio Mussolino. « Chimerization Enables Gene Synthesis and Lentiviral Delivery of Customizable TALE-Based Effectors ». International Journal of Molecular Sciences 21, no 3 (25 janvier 2020) : 795. http://dx.doi.org/10.3390/ijms21030795.
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Designer effectors based on the DNA binding domain (DBD) of Xanthomonas transcription activator-like effectors (TALEs) are powerful sequence-specific tools with an excellent reputation for their specificity in editing the genome, transcriptome, and more recently the epigenome in multiple cellular systems. However, the repetitive structure of the TALE arrays composing the DBD impedes their generation as gene synthesis product and prevents the delivery of TALE-based genes using lentiviral vectors (LVs), a widely used system for human gene therapy. To overcome these limitations, we aimed at chimerizing the DNA sequence encoding for the TALE-DBDs by introducing sufficient diversity to facilitate both their gene synthesis and enable their lentiviral delivery. To this end, we replaced three out of 17 Xanthomonas TALE repeats with TALE-like units from the bacterium Burkholderia rhizoxinica. This was combined with extensive codon variation and specific amino acid substitutions throughout the DBD in order to maximize intra- and inter-repeat sequence variability. We demonstrate that chimerized TALEs can be easily generated using conventional Golden Gate cloning strategy or gene synthesis. Moreover, chimerization enabled the delivery of TALE-based designer nucleases, transcriptome and epigenome editors using lentiviral vectors. When delivered as plasmid DNA, chimerized TALEs targeting the CCR5 and CXCR4 loci showed comparable activities in human cells. However, lentiviral delivery of TALE-based transcriptional activators was only successful in the chimerized form. Similarly, delivery of a chimerized CXCR4-specific epigenome editor resulted in rapid silencing of endogenous CXCR4 expression. In conclusion, extensive codon variation and chimerization of TALE-based DBDs enables both the simplified generation and the lentiviral delivery of designer TALEs, and therefore facilitates the clinical application of these tools to precisely edit the genome, transcriptome and epigenome.
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Roman Azcona, Maria Silvia, Yongxing Fang, Antonio Carusillo, Toni Cathomen et Claudio Mussolino. « A versatile reporter system for multiplexed screening of effective epigenome editors ». Nature Protocols 15, no 10 (4 septembre 2020) : 3410–40. http://dx.doi.org/10.1038/s41596-020-0380-y.
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Willyard, Cassandra. « The epigenome editors : How tools such as CRISPR offer new details about epigenetics ». Nature Medicine 23, no 8 (août 2017) : 900–903. http://dx.doi.org/10.1038/nm0817-900.
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O’Geen, Henriette, Marketa Tomkova, Jacquelyn A. Combs, Emma K. Tilley et David J. Segal. « Determinants of heritable gene silencing for KRAB-dCas9 + DNMT3 and Ezh2-dCas9 + DNMT3 hit-and-run epigenome editing ». Nucleic Acids Research 50, no 6 (2 mars 2022) : 3239–53. http://dx.doi.org/10.1093/nar/gkac123.
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Abstract Precision epigenome editing has gained significant attention as a method to modulate gene expression without altering genetic information. However, a major limiting factor has been that the gene expression changes are often transient, unlike the life-long epigenetic changes that occur frequently in nature. Here, we systematically interrogate the ability of CRISPR/dCas9-based epigenome editors (Epi-dCas9) to engineer persistent epigenetic silencing. We elucidated cis regulatory features that contribute to the differential stability of epigenetic reprogramming, such as the active transcription histone marks H3K36me3 and H3K27ac strongly correlating with resistance to short-term repression and resistance to long-term silencing, respectively. H3K27ac inversely correlates with increased DNA methylation. Interestingly, the dependance on H3K27ac was only observed when a combination of KRAB-dCas9 and targetable DNA methyltransferases (DNMT3A-dCas9 + DNMT3L) was used, but not when KRAB was replaced with the targetable H3K27 histone methyltransferase Ezh2. In addition, programmable Ezh2/DNMT3A + L treatment demonstrated enhanced engineering of localized DNA methylation and was not sensitive to a divergent chromatin state. Our results highlight the importance of local chromatin features for heritability of programmable silencing and the differential response to KRAB- and Ezh2-based epigenetic editing platforms. The information gained in this study provides fundamental insights into understanding contextual cues to more predictably engineer persistent silencing.
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Psatha, Nikoletta, Kiriaki Paschoudi, Anastasia Papadopoulou et Evangelia Yannaki. « In Vivo Hematopoietic Stem Cell Genome Editing : Perspectives and Limitations ». Genes 13, no 12 (27 novembre 2022) : 2222. http://dx.doi.org/10.3390/genes13122222.
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The tremendous evolution of genome-editing tools in the last two decades has provided innovative and effective approaches for gene therapy of congenital and acquired diseases. Zinc-finger nucleases (ZFNs), transcription activator- like effector nucleases (TALENs) and CRISPR-Cas9 have been already applied by ex vivo hematopoietic stem cell (HSC) gene therapy in genetic diseases (i.e., Hemoglobinopathies, Fanconi anemia and hereditary Immunodeficiencies) as well as infectious diseases (i.e., HIV), and the recent development of CRISPR-Cas9-based systems using base and prime editors as well as epigenome editors has provided safer tools for gene therapy. The ex vivo approach for gene addition or editing of HSCs, however, is complex, invasive, technically challenging, costly and not free of toxicity. In vivo gene addition or editing promise to transform gene therapy from a highly sophisticated strategy to a “user-friendly’ approach to eventually become a broadly available, highly accessible and potentially affordable treatment modality. In the present review article, based on the lessons gained by more than 3 decades of ex vivo HSC gene therapy, we discuss the concept, the tools, the progress made and the challenges to clinical translation of in vivo HSC gene editing.
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Dehshahri, Ali, Alessio Biagioni, Hadi Bayat, E. Hui Clarissa Lee, Mohammad Hashemabadi, Hojjat Samareh Fekri, Ali Zarrabi, Reza Mohammadinejad et Alan Prem Kumar. « Editing SOX Genes by CRISPR-Cas : Current Insights and Future Perspectives ». International Journal of Molecular Sciences 22, no 21 (20 octobre 2021) : 11321. http://dx.doi.org/10.3390/ijms222111321.
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Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and its associated proteins (Cas) is an adaptive immune system in archaea and most bacteria. By repurposing these systems for use in eukaryote cells, a substantial revolution has arisen in the genome engineering field. In recent years, CRISPR-Cas technology was rapidly developed and different types of DNA or RNA sequence editors, gene activator or repressor, and epigenome modulators established. The versatility and feasibility of CRISPR-Cas technology has introduced this system as the most suitable tool for discovering and studying the mechanism of specific genes and also for generating appropriate cell and animal models. SOX genes play crucial roles in development processes and stemness. To elucidate the exact roles of SOX factors and their partners in tissue hemostasis and cell regeneration, generating appropriate in vitro and in vivo models is crucial. In line with these premises, CRISPR-Cas technology is a promising tool for studying different family members of SOX transcription factors. In this review, we aim to highlight the importance of CRISPR-Cas and summarize the applications of this novel, promising technology in studying and decoding the function of different members of the SOX gene family.
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Szyf, Moshe. « The Epigenome : Molecular Hide and Seek. Stephan Beck and Alexander Olek, editors. Weinheim, Germany : Wiley-VCH GmbH Co. KGaA, 2003, 188 pp., $35.00, softcover. ISBN 3-527-30494-0. » Clinical Chemistry 49, no 9 (1 septembre 2003) : 1566–67. http://dx.doi.org/10.1373/49.9.1566.
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Brane, Andrew, Madeline Sutko et Trygve O. Tollefsbol. « p21 Promoter Methylation Is Vital for the Anticancer Activity of Withaferin A ». International Journal of Molecular Sciences 26, no 3 (30 janvier 2025) : 1210. https://doi.org/10.3390/ijms26031210.
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Breast cancer (BC) is a widespread malignancy that affects the lives of millions of women each year, and its resulting financial and healthcare hardships cannot be overstated. These issues, in combination with side effects and obstacles associated with the current standard of care, generate considerable interest in new potential targets for treatment as well as means for BC prevention. One potential preventive compound is Withaferin A (WFA), a traditional medicinal compound found in winter cherries. WFA has shown promise as an anticancer agent and is thought to act primarily through its effects on the epigenome, including, in particular, the methylome. However, the relative importance of specific genes’ methylation states to WFA function remains unclear. To address this, we utilized human BC cell lines in combination with CRISPR-dCas9 fused to DNA methylation modifiers (i.e., epigenetic editors) to elucidate the importance of specific genes’ promoter methylation states to WFA function and cancer cell viability. We found that targeted demethylation of promoters of the tumor suppressors p21 and p53 within MDA-MB-231/MCF7 cells resulted in around 1.7×/1.5× and 1.2×/1.3× increases in expression, respectively. Targeted methylation of the promoter of the oncogene CCND1 within MDA-MB-231/MCF7 cells resulted in 0.5×/0.8× decreases in gene expression. These changes to p21, p53, and CCND1 were also associated with decreases in cell viability of around 25%/50%, 5%/35%, and 12%/16%, respectively, for MDA-MB-231/MCF7 cells. When given in combination with WFA in both p53 mutant and wild type cells, we discovered that targeted methylation of the p21 promoter was able to modulate the anticancer effects of WFA, while targeted methylation or demethylation of the promoters of p53 and CCND1 had no significant effect on viability decreases from WFA treatment. Taken together, these results indicate that p21, p53, and CCND1 may be important targets for future in vivo studies that may lead to epigenetic editing therapies and that WFA may have utility in the prevention of BC through its effect on p21 promoter methylation independent of p53 function.
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Zaenker, Kurt. « Editorial From Editor-in-Chief : The Epigenome ». Epigenetic Diagnosis & ; Therapy 1, no 1 (17 avril 2015) : 2. http://dx.doi.org/10.2174/221408320101150417114249.
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Goodrich, Jaclyn. « Insights on exposure-induced disease susceptibility : an interview with Jaclyn Goodrich ». Epigenomics 14, no 6 (mars 2022) : 319–21. http://dx.doi.org/10.2217/epi-2022-0046.
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In this interview, Dr Jaclyn Goodrich speaks with Storm Johnson, Commissioning Editor for Epigenomics, on her work to date on environmental epigenetics and the impact of toxic exposures on susceptible populations. Jaclyn Goodrich is a research assistant professor of environmental health sciences at the University of Michigan School of Public Health (Ann Arbor, MI, USA). She obtained a doctorate in toxicology and completed postdoctoral training in environmental epigenomics at the University of Michigan. The overarching goal of her current research program is to identify environmental factors that modify the epigenome and increase risk for disease throughout the life course. She primarily conducts epidemiological studies to investigate the impact of toxic exposures on susceptible populations including children and occupationally exposed workers. She has coauthored more than 70 publications and is an active member of the Society of Toxicology and the Environmental Mutagenesis and Genomics Society.
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Yusuf, Abdurrahman Pharmacy, Murtala Bello Abubakar, Ibrahim Malami, Kasimu Ghandi Ibrahim, Bilyaminu Abubakar, Muhammad Bashir Bello, Naeem Qusty et al. « Zinc Metalloproteins in Epigenetics and Their Crosstalk ». Life 11, no 3 (26 février 2021) : 186. http://dx.doi.org/10.3390/life11030186.
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More than half a century ago, zinc was established as an essential micronutrient for normal human physiology. In silico data suggest that about 10% of the human proteome potentially binds zinc. Many proteins with zinc-binding domains (ZBDs) are involved in epigenetic modifications such as DNA methylation and histone modifications, which regulate transcription in physiological and pathological conditions. Zinc metalloproteins in epigenetics are mainly zinc metalloenzymes and zinc finger proteins (ZFPs), which are classified into writers, erasers, readers, editors, and feeders. Altogether, these classes of proteins engage in crosstalk that fundamentally maintains the epigenome’s modus operandi. Changes in the expression or function of these proteins induced by zinc deficiency or loss of function mutations in their ZBDs may lead to aberrant epigenetic reprogramming, which may worsen the risk of non-communicable chronic diseases. This review attempts to address zinc’s role and its proteins in natural epigenetic programming and artificial reprogramming and briefly discusses how the ZBDs in these proteins interact with the chromatin.
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Gupta, Pravesh, Dapeng Hao, Krishna Bojja Bojja, Tuan Tran, Minghao Dang, Jianzhuo Li, Atul Maheshwari, Nicholas Navin, Linghua Wang et Krishna Bhat. « 833 The epigenomic landscape of human glioma-associated myeloid cells ». Journal for ImmunoTherapy of Cancer 8, Suppl 3 (novembre 2020) : A885. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0833.
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BackgroundGliomas are recalcitrant tumors of the central nervous system. The tumor immune microenvironment (TIME) in gliomas is considered immunosuppressive and making it difficult to treat these tumors with conventional immunotherapy approaches, therefore a better characterization of the immune cell repertoire is needed to fully understand the tumor immune contexture. While single-cell RNA-sequencing (scRNA-seq) approaches have revealed the transcriptional heterogeneity, the gene regulatory landscape at the chromatin level is quintessential for a deeper understanding of lineage and signal-dependent transcription factors (TFs) induced in the brain TIME.MethodsWe performed single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) on ~90,000 tumor-associated and sorted CD45+ leukocytes from fourteen genomically classified patients comprising IDH-mutant primary (IMP; n=4), IDH-mutant recurrent (IMR; n=3), IDH-wild type primary (IWP; n=3), or IDH-wild type recurrent (IWR; n=4) gliomas (hereafter referred as glioma subtypes) and two non-glioma brains (NGBs) as controls. The resulting data were quality checked and processed using Cell Ranger ATAC-seq pipeline and trajectory analyses were performed using Monocle2.ResultsUsing scRNA-seq data from matched specimens and gene tagging approaches, we identified twenty-six clusters of myeloid and seventeen clusters of lymphoid populations across and within gliomas. In this study, we exclusively focused on myeloid subpopulations, which were resolved into microglia and non-microglia myeloid cell subsets. Concordant with our scRNA-seq data, we identified all cell types including monocytes, monocyte-derived cells (MDCs), and dendritic cells by using differential gene accessibility (DGE) analyses. Importantly, although MG from all samples clustered differently, NGB and IM subtypes exhibited concordance in DGE and were separate from IWP and IWR subtypes. Reconstruction of the cell trajectories demonstrated that enhancers for TFs related to mesenchymal transition in GBM such as NF-kB and CEBPB were accessible from normal to tumor-associated microglia. On the other hand, tissue-associated macrophages exhibited enhanced calcium-regulated NFAT TF accessibility. Tumor-associated IWP and IWR myeloid cells also showed a gain of DGE of apoptosis and a reduction of proliferation-related genes.ConclusionsOur studies demonstrate that in addition to the previous dogma of myeloid mediated immune suppression that contributes to tumor immune escape, epigenomic reprogramming in the brain TIME leads to unexpected activation of transcriptional pathways that can trigger transdifferentiation and cell death of myeloid cells further promoting tumor progression. In summary, we provide an unparalleled epigenomic landscape of glioma-associated myeloid cells that may have translational implications.AcknowledgementsThis study in Krishna Bhat’s laboratory was supported by the generous philanthropic contributions to The University of Texas (UT) MD Anderson Cancer Center (MDACC) Moon Shots Program™, Marnie Rose Foundation, NIH grants: R21 CA222992 and R01CA225963. This study was partly supported by the UT MDACC start-up research fund to Linghua Wang and CPRIT Single-Core grant RP180684 to Nicholas Navin.Trial RegistrationNAEthics ApprovalThe brain tumor/tissue samples were collected as per MD Anderson internal review board (IRB)-approved protocol numbers LAB03-0687 and, LAB04-0001. One non-tumor brain tissue sample was collected from a patient undergoing neurosurgery for epilepsy as per Baylor College of Medicine IRB-approved protocol number H-13798. All experiments were compliant with the review board of MD Anderson Cancer Center, USA.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal
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Jirtle, Randy L. « The science of hope : an interview with Randy Jirtle ». Epigenomics 14, no 6 (mars 2022) : 299–302. http://dx.doi.org/10.2217/epi-2022-0048.
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In this interview, Professor Randy L Jirtle speaks with Storm Johnson, Commissioning Editor for Epigenomics, on his work on genomic imprinting, environmental epigenomics and the fetal origins of disease susceptibility. Professor Randy Jirtle joined the Duke University Department of Radiology in 1977 and headed the Epigenetics and Imprinting Laboratory until 2012. He is now Professor of Epigenetics in the Department of Biological Sciences at North Carolina State University, Raleigh, NC, USA. Jirtle's research interests are in epigenetics, genomic imprinting and the fetal origins of disease susceptibility. He is known for his groundbreaking studies linking environmental exposures early in life to the development of adult diseases through changes in the epigenome and for determining the evolutionary origin of genomic imprinting in mammals. He has published over 200 peer-reviewed articles as well as the books Liver Regeneration and Carcinogenesis: Molecular and Cellular Mechanisms, Environmental Epigenomics in Health and Disease: Epigenetics and Disease Origins and Environmental Epigenomics in Health and Disease: Epigenetics and Complex Diseases. He was honored in 2006 with the Distinguished Achievement Award from the College of Engineering at the University of Wisconsin-Madison. In 2007, he was a featured scientist on the NOVA television program on epigenetics titled ‘Ghost in Your Genes’ and was nominated for Time Magazine's ‘Person of the Year’. He was the inaugural recipient of the Epigenetic Medicine Award in 2008 and received the STARS Lecture Award in Nutrition and Cancer from the National Cancer Institute in 2009. Jirtle was presented the Linus Pauling Award from the Institute of Functional Medicine in 2014. In 2017, ShortCutsTV produced the English documentary ‘Are You What Your Mother Ate? The Agouti Mouse Study’ based on his pioneering epigenetic research. He received the 2018 Northern Communities Health Foundation Visiting Professorship Award at the University of Adelaide, Australia. The Personalized Lifestyle Medicine Institute presented Jirtle with the Research and Innovation Leadership Award in 2019. Dr Jirtle was also given the Alexander Hollaender Award in 2019 at the 50th annual meeting of the Environmental Mutagenesis and Genomics Society.
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Laird, Peter W. « How epigenomics broke the mold : an interview with Peter W Laird ». Epigenomics 14, no 6 (mars 2022) : 303–8. http://dx.doi.org/10.2217/epi-2022-0066.
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In this interview, Professor Peter W Laird speaks with Storm Johnson, Commissioning Editor for Epigenomics, on his work to date in the field of cancer epigenetics. Dr Peter W Laird is a Professor at Van Andel Institute (VAI) in Grand Rapids, Michigan. He earned his B.S. and M.S., Cum Laude, from the University of Leiden, The Netherlands. He trained for his PhD with Dr Piet Borst, The Netherlands Cancer Institute, and as a postdoc with Dr Anton Berns, The Netherlands Cancer Institute, and with Dr Rudolf Jaenisch, at the Whitehead Institute for Biomedical Research in Cambridge, MA, USA. He joined the faculty at the University of Southern California in 1996, where he served as the Founding Director of the USC Epigenome Center and also as the Leader of the Epigenetics and Regulation Program of the Norris Comprehensive Cancer Center. In 2014, he relocated to VAI to join Dr Peter Jones in building an internationally acclaimed research center focused on Epigenetics. Dr Laird published the first demonstration of the causal role for DNA methylation in oncogenesis ( Cell, 1995) [ 1 ]. He served as the Principal Investigator for all DNA methylation data production for the Cancer Genome Atlas (TCGA) and led many TCGA analysis efforts. He has been awarded 10 patents related to DNA methylation technology by the United States Patent and Trademark Office, one of which is the basis for the first US FDA-approved blood-based DNA methylation assay for cancer (Epi proColon). His research findings include the report of a close link between DNA methylation and BRAF mutation in colorectal cancer ( Nature Genetics, 2006) [ 2 ], the discovery that embryonic stem cell polycomb repressor targets are predisposed to abnormal DNA methylation in cancer ( Nature Genetics, 2007) [ 3 ], the identification of a novel epigenetic subtype of glioma (G-CIMP), tightly associated with IDH1 mutation ( Cancer Cell, 2010) [ 4 ], and the connection between nuclear architecture, late replication, and domains of epigenetic instability ( Nature Genetics, 2011) [ 5 ], later showing a link with mitotic cell division, thus providing a mechanistic explanation for the loss of DNA methylation in aging and cancer first described four decades ago ( Nature Genetics, 2018) [ 6 ].
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Goel, Ajay. « The era of biomarkers and precision medicine in colorectal cancer : an interview with Ajay Goel ». Epigenomics 14, no 6 (mars 2022) : 345–49. http://dx.doi.org/10.2217/epi-2022-0010.
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In this interview, Professor Ajay Goel speaks with Storm Johnson, Commissioning Editor for Epigenomics, on his work to date in the field of epigenetic biomarkers in colorectal cancer. Ajay Goel, PhD, is a Professor and Founding Chair of the Department of Molecular Diagnostics, at the Beckman Research Institute and Associate Director of Basic Science at the City of Hope comprehensive Cancer Center. He also serves as Director of Biotech Innovations at the City of Hope, Duarte, CA, USA. Dr Goel has spent more than 25 years researching cancer and has been the lead author or contributor to more than 350 scientific articles published in peer-reviewed international journals and several book chapters. He is also a primary inventor on more than 40 international patents aimed at developing various disease biomarkers or therapeutic targets for gastrointestinal cancers. He is currently using advanced genomic, epigenomic and transcriptomic approaches to develop novel circulating, liquid biopsy-based biomarkers (e.g., cell-free nucleic acids, exosomes) for the early detection, prognosis and determination of predictive responses to chemotherapy and targeted drugs in gastrointestinal (GI) cancers. In addition, his group is interested in the identification of novel therapeutic targets, particularly immune therapy, for various GI cancers. His research also involves understanding the role of gut microbiome, health disparities and the prevention of GI cancers using integrative and alternative approaches. Dr Goel is a member of the American Association for Cancer Research, American Society of Clinical Oncology and the American Gastroenterology Association. He is on the international editorial boards of several journals, including Gastroenterology, Clinical Cancer Research, Carcinogenesis, PLoS ONE, Molecular Carcinogenesis, Scientific Reports, Epigenomics, Future Oncology, Alternative Therapies in Heath and Medicine, Digestive Diseases and Sciences, and Molecular Therapy Oncolytics. He is also actively involved in peer-reviewing activities for more than 100 international scientific journals and various grant review panels of various national and international funding organizations. His research has been actively funded by various private and federal organizations, including the National Cancer Institute at the NIH, American Cancer Society and state organizations. He has won more than a dozen national and international awards and honors and has been invited for visiting professorships by various national and international academic institutions and academic bodies.
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« Fine-tuning epigenome editors ». Nature Biotechnology 40, no 3 (mars 2022) : 281. http://dx.doi.org/10.1038/s41587-022-01270-w.
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Cappelluti, Martino Alfredo, Valeria Mollica Poeta, Sara Valsoni, Piergiuseppe Quarato, Simone Merlin, Ivan Merelli et Angelo Lombardo. « Durable and efficient gene silencing in vivo by hit-and-run epigenome editing ». Nature, 28 février 2024. http://dx.doi.org/10.1038/s41586-024-07087-8.
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AbstractPermanent epigenetic silencing using programmable editors equipped with transcriptional repressors holds great promise for the treatment of human diseases1–3. However, to unlock its full therapeutic potential, an experimental confirmation of durable epigenetic silencing after the delivery of transient delivery of editors in vivo is needed. To this end, here we targeted Pcsk9, a gene expressed in hepatocytes that is involved in cholesterol homeostasis. In vitro screening of different editor designs indicated that zinc-finger proteins were the best-performing DNA-binding platform for efficient silencing of mouse Pcsk9. A single administration of lipid nanoparticles loaded with the editors’ mRNAs almost halved the circulating levels of PCSK9 for nearly one year in mice. Notably, Pcsk9 silencing and accompanying epigenetic repressive marks also persisted after forced liver regeneration, further corroborating the heritability of the newly installed epigenetic state. Improvements in construct design resulted in the development of an all-in-one configuration that we term evolved engineered transcriptional repressor (EvoETR). This design, which is characterized by a high specificity profile, further reduced the circulating levels of PCSK9 in mice with an efficiency comparable with that obtained through conventional gene editing, but without causing DNA breaks. Our study lays the foundation for the development of in vivo therapeutics that are based on epigenetic silencing.
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Yahsi, Berkay, Fahreddin Palaz et Pervin Dincer. « Applications of CRISPR Epigenome Editors in Tumor Immunology and Autoimmunity ». ACS Synthetic Biology, 31 janvier 2024. http://dx.doi.org/10.1021/acssynbio.3c00524.
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Dhakate, Priyanka, Deepmala Sehgal, Samantha Vaishnavi, Atika Chandra, Apekshita Singh, Soom Nath Raina et Vijay Rani Rajpal. « Comprehending the evolution of gene editing platforms for crop trait improvement ». Frontiers in Genetics 13 (23 août 2022). http://dx.doi.org/10.3389/fgene.2022.876987.
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CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas (CRISPR-associated) system was initially discovered as an underlying mechanism for conferring adaptive immunity to bacteria and archaea against viruses. Over the past decade, this has been repurposed as a genome-editing tool. Numerous gene editing-based crop improvement technologies involving CRISPR/Cas platforms individually or in combination with next-generation sequencing methods have been developed that have revolutionized plant genome-editing methodologies. Initially, CRISPR/Cas nucleases replaced the earlier used sequence-specific nucleases (SSNs), such as zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), to address the problem of associated off-targets. The adaptation of this platform led to the development of concepts such as epigenome editing, base editing, and prime editing. Epigenome editing employed epi-effectors to manipulate chromatin structure, while base editing uses base editors to engineer precise changes for trait improvement. Newer technologies such as prime editing have now been developed as a “search-and-replace” tool to engineer all possible single-base changes. Owing to the availability of these, the field of genome editing has evolved rapidly to develop crop plants with improved traits. In this review, we present the evolution of the CRISPR/Cas system into new-age methods of genome engineering across various plant species and the impact they have had on tweaking plant genomes and associated outcomes on crop improvement initiatives.
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Verma, Vipasha, Akhil Kumar, Mahinder Partap, Meenakshi Thakur et Bhavya Bhargava. « CRISPR-Cas : A robust technology for enhancing consumer-preferred commercial traits in crops ». Frontiers in Plant Science 14 (7 février 2023). http://dx.doi.org/10.3389/fpls.2023.1122940.
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The acceptance of new crop varieties by consumers is contingent on the presence of consumer-preferred traits, which include sensory attributes, nutritional value, industrial products and bioactive compounds production. Recent developments in genome editing technologies provide novel insight to identify gene functions and improve the various qualitative and quantitative traits of commercial importance in plants. Various conventional as well as advanced gene-mutagenesis techniques such as physical and chemical mutagenesis, CRISPR-Cas9, Cas12 and base editors are used for the trait improvement in crops. To meet consumer demand, breakthrough biotechnologies, especially CRISPR-Cas have received a fair share of scientific and industrial interest, particularly in plant genome editing. CRISPR-Cas is a versatile tool that can be used to knock out, replace and knock-in the desired gene fragments at targeted locations in the genome, resulting in heritable mutations of interest. This review highlights the existing literature and recent developments in CRISPR-Cas technologies (base editing, prime editing, multiplex gene editing, epigenome editing, gene delivery methods) for reliable and precise gene editing in plants. This review also discusses the potential of gene editing exhibited in crops for the improvement of consumer-demanded traits such as higher nutritional value, colour, texture, aroma/flavour, and production of industrial products such as biofuel, fibre, rubber and pharmaceuticals. In addition, the bottlenecks and challenges associated with gene editing system, such as off targeting, ploidy level and the ability to edit organelle genome have also been discussed.
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Bode, Daniel, Alyssa H. Cull, Juan A. Rubio-Lara et David G. Kent. « Exploiting Single-Cell Tools in Gene and Cell Therapy ». Frontiers in Immunology 12 (12 juillet 2021). http://dx.doi.org/10.3389/fimmu.2021.702636.
Texte intégralRésumé :
Single-cell molecular tools have been developed at an incredible pace over the last five years as sequencing costs continue to drop and numerous molecular assays have been coupled to sequencing readouts. This rapid period of technological development has facilitated the delineation of individual molecular characteristics including the genome, transcriptome, epigenome, and proteome of individual cells, leading to an unprecedented resolution of the molecular networks governing complex biological systems. The immense power of single-cell molecular screens has been particularly highlighted through work in systems where cellular heterogeneity is a key feature, such as stem cell biology, immunology, and tumor cell biology. Single-cell-omics technologies have already contributed to the identification of novel disease biomarkers, cellular subsets, therapeutic targets and diagnostics, many of which would have been undetectable by bulk sequencing approaches. More recently, efforts to integrate single-cell multi-omics with single cell functional output and/or physical location have been challenging but have led to substantial advances. Perhaps most excitingly, there are emerging opportunities to reach beyond the description of static cellular states with recent advances in modulation of cells through CRISPR technology, in particular with the development of base editors which greatly raises the prospect of cell and gene therapies. In this review, we provide a brief overview of emerging single-cell technologies and discuss current developments in integrating single-cell molecular screens and performing single-cell multi-omics for clinical applications. We also discuss how single-cell molecular assays can be usefully combined with functional data to unpick the mechanism of cellular decision-making. Finally, we reflect upon the introduction of spatial transcriptomics and proteomics, its complementary role with single-cell RNA sequencing (scRNA-seq) and potential application in cellular and gene therapy.
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Conroy, Gemma. « ‘Epigenome editor’ silences gene that causes deadly brain disorders ». Nature, 27 juin 2024. http://dx.doi.org/10.1038/d41586-024-02115-z.
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« An interview with Peter Rugg-Gunn ». Development 151, no 14 (12 juillet 2024). http://dx.doi.org/10.1242/dev.204218.
Texte intégralRésumé :
Peter Rugg-Gunn is a Group Leader and Head of Public Engagement at the Babraham Institute in Cambridge, UK, interested in the epigenome during early human development. Peter is scientific lead of the Human Developmental Biology Initiative (HDBI), a member of the Scientific and Clinical Advances Advisory Committee of the Human Fertilisation and Embryology Authority (HFEA), and is active in UK and international efforts to establish guidance in stem cell-based embryo models. We spoke to Peter about his career path, his interest in public dialogue and his role as an Editor for Development.
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Zahir, Farah R. « Understanding environmental epigenomics in autism spectrum disorder : an interview with Farah R Zahir ». Epigenomics, 23 septembre 2021. http://dx.doi.org/10.2217/epi-2021-0319.
Texte intégralRésumé :
In this interview, Dr Farah R Zahir speaks with Storm Johnson, Commissioning Editor for Epigenomics, on her work to date in the field of epigenomics, autism and intellectual disability. Dr Farah R Zahir specializes in the identification of novel genetic and epigenetic causes for neurodevelopmental diseases. Her PhD, awarded in 2011 by the University of British Columbia (UBC), resulted in the characterization of new intellectual disability (ID) syndromes, as well as discovery of several new causative genes for the disorder. She was awarded the prestigious James Miller Memorial Prize for integrating basic and clinical science in 2010. Her PhD dissertation was nominated for the Governor General’s gold medal – the highest possible accolade at UBC for doctoral research work. She then completed a postdoctoral tenure in Canada’s premier Michael Smith Genome Sciences Centre, where she used whole-genome-sequencing methods to comprehensively assess genetic, molecular and structural causes for ID, employing several firsts for bioinformatic data mining in the field. During her postdoctorate she won three distinguished awards and was a fellow of the Canadian Institute of Health Research, ranking in the top 2% nationally. Dr Zahir was appointed an Assistant Professor at the Hamad Bin Khalifa University in 2016, where she led a group focused on neurogenomics and neuroepigenomics research. She was a founding member of the Precision and Genomics Medicine graduate program there. Currently she has rejoined UBC's department of Medical Genetics. Among her most significant achievements is the establishment of the novel Zahir Friedman syndrome, an intellectual disability/autism spectrum disorder syndrome that is caused by a major epigenomic regulator. Her current primary research interest is how epigenomics can be changed by environmental impacts and how these effects may be harnessed for neurodevelopmental disorders' prophylaxis and therapeutics.