Iva Tchasovnikarova
Group leaderResearch summary
Genetic interrogation of epigenetic pathways
We study epigenetic pathways and the mechanisms through which these processes are corrupted by disease-associated mutations in chromatin regulators. We aim to (1) understand the mechanisms utilised by chromatin modifiers to exert their function in healthy human cells, and (2) examine how these mechanisms are altered in human disorders in molecular detail.
Why what we do is important
Epigenetic modifications of DNA, RNA and histones are important regulators of all DNA-templated processes, including transcription, DNA repair and replication. Disruption of these epigenetic pathways is therefore commonly observed in a variety of human conditions, such as developmental disorders and cancer. The reversible nature of these disruptions has made epigenetic regulators attractive targets for therapeutic manipulation. However, a detailed understanding of the fundamental biology underlying these epigenetic mechanisms is still needed to delineate the optimal targets for future therapeutic manipulation.
How we do it
We use high-throughput genetic technologies, such as CRISPR/Cas9 forward genetic screens, to discover novel factors involved in chromatin regulation. To dissect the mechanism of action of these factors, we take advantage of established genetic and biochemical approaches. In addition, a major focus of the lab is to develop novel genetic technologies to characterise epigenetic pathways in human cells.
A genome-wide CRISPR/Cas9 screen to identify genes required for transgene silencing. Six genes are required for epigenetic silencing of a repressed GFP reporter: the three HUSH complex subunits TASOR, MPP8 and Periphilin; the H3K9 methyltransferase SETDB1 and its binding partner ATF7IP; and the chromatin remodeller MORC2.
Selected publications
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Tchasovnikarova IA et al. (2021) TRACE generates fluorescent human reporter cell lines to characterize epigenetic pathways. Molecular Cell 82: 479–491.e7. DOI: 10.1016/j.molcel.2021.11.035.
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Douse CH et al. (2020) TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control. Nature Communications, 11: 4940. DOI: 10.1038/s41467-020-18761-6.
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Guillen Sacoto MJ et al. (2020) De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism. Am J Hum Gen 107: 352-363. DOI: 10.1016/j.ajhg.2020.06.013.
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Timms RT et al. (2019) Differential Viral Accessibility (DIVA) identifies alterations in chromatin architecture through large-scale mapping of lentiviral integration sites. Nat Protoc 14: 153–170. DOI: 10.1038/s41596-018-0087-5.
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Tchasovnikarova IA et al. (2017) Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2. Nat Genet 49: 1035–1044. DOI:10.1038/ng.3878.
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Tchasovnikarova IA et al. (2015) Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science 348: 1481–1485. DOI: 10.1126/science.aaa7227.
Biography
Iva Tchasovnikarova PhD
Group Leader, Member of the University Department of Biochemistry
Originally from Bulgaria, Iva moved to the UK to study Biotechnology at the University of Edinburgh. She then joined the laboratory of Prof. Paul Lehner at the Cambridge Institute for Medical Research at the University of Cambridge, as part of the Wellcome Trust Infection and Immunity 4-year PhD programme. There, she performed a series of haploid gene-trap mutagenesis and CRISPR/Cas9-mediated forward genetic screens which identified a novel epigenetic repressor complex, HUSH, as the key mediator of position-effect variegation in human cells.
In 2016, Iva joined the laboratory of Dr Robert Kingston at Massachusetts General Hospital/Harvard Medical School as a fellow of the Damon Runyon Cancer Research Foundation. There, she leveraged her experience with genetic technologies to develop a genome-wide method to study chromatin accessibility (DIVA), as well as an unbiased method that allows for the identification of fluorescent, cell-based reporters of chromatin states (TRACE). Dr Tchasovnikarova joined the Gurdon Institute as a Group Leader in 2020.
Notable achievements and honours
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2020Damon Runyon-Dale F. Frey Award for Breakthrough Scientists
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2016Damon Runyon Cancer Research Foundation Postdoctoral Fellowship
Research group
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Dr Laura Farleigh Smith
Lab Manager/ Research Assistant
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Rachael Matthews
PhD Student
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Chuyan Qin
PhD Student
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