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The Gurdon Institute

 

2019 Tchasovnikarova

Iva A. Tchasovnikarova, PhD

Group Leader in Cancer Biology

Damon Runyon-Dale F. Frey Breakthrough Scientist

Tchasovnikarova Group websiteEurope PMC | PubMed 

  

 

Genetic interrogation of epigenetic pathways

What We Do

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.

 Some examples of the type of approaches we use are:

  • Genetically encoded fluorescent reporters 
  • CRISPR/Cas9 forward genetic screens
  • CRISPR-mediated genome editing
  • CRISPRi and CRISPRa
  • Next-generation sequencing
  • Flow cytometry
  • Immunofluorescence microscopy
  • Chromatin immunoprecipitation (ChIP)

 

Selected publications:

  • Douse CH*, Tchasovnikarova IA*, Timms RT*, Protasio AV, Seczynska M, Prigozhin DM, Albecka A, Wagstaff J, Williamson JC, Freund SMV, Lehner PJ, Modis Y (2020) TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control. Nature Communications11: 4940.

  • Prigozhin DM, Douse CH, Farleigh LE, Albecka A, Tchasovnikarova IA, Timms RT, Oda S, Adolf F, Freund SMV, Maslen S, Lehner PJ, Modis Y (2020) Periphilin self-association underpins epigenetic silencing by the HUSH complex. Nucleic Acids Research48 (18): 10313-10328.

  • Guillen Sacoto, Tchasovnikarova IA et al. (2020) De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism. The American Journal of Human Genetics107 (2): 352-363.

  • Timms RT, Tchasovnikarova IA, Lehner PJ (2019) Differential Viral Accessibility (DIVA) identifies alterations in chromatin architecture through large-scale mapping of lentiviral integration sites. Nature Protocols14: 153-170.
  • Tchasovnikarova IA, Kingston RE (2018) Beyond the Histone Code: A Physical Map of Chromatin States. Molecular Cell69: 5-7
  • Tchasovnikarova IA, Timms RT, Douse CH, Roberts CR, Dougan G, Kingston RE, Modis Y, Lehner PJ (2017) Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2. Nature Genetics49: 1035-1044
  • Timms RT, Tchasovnikarova IA, Antrobus R, Dougan G, Lehner PJ (2016) ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex. Cell Reports17 (3): 653-659
  • Timms RT, Tchasovnikarova IA, Lehner PJ (2016) Position-effect variegation revisited: HUSHing up heterochromatin in human cells. Bioessays38 (4): 333-343 (invited review article)
  • Tchasovnikarova IA, Timms RT, Matheson NJ, Wals K, Antrobus R, Göttgens B, Dougan G, Dawson MA, Lehner PJ (2015) Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science,348 (6242): 1481-5

Co-workers

Lynn Froggett