Control of gene expression holds great promise for genome biology research and also as a new strategy for better treatment of human diseases caused by dysfunction of genes. However, currently, we lack a technology that is capable of modulating gene expression at the level of transcription in a reversible manner. Notably, recent advances in epigenetics have greatly enhanced our understanding on how site-specific chemical modifications in DNA-packing histones control gene expression in response to physiological and environmental stimuli. Specifically, in our own research, we have discovered a novel viral mechanism that controls host gene transcription through histone methylation. We show that chlorella virus uses a viral protein (termed vSET) to modify histone H3 at lysine 27 (H3K27) in the infected cells, thereby shutting down host transcription. Consistent with the fact that H3K27 methylation is a conserved epigenetic mark for gene transcriptional silencing in metazoa, vSET can effectively suppress gene transcription normally targeted by the Polycomb group proteins in human cells. Given its high selectivity for H3K27 methylation, vSET could in principle be developed into a highly selective epigenetic gene silencing technology by fusing to a gene-specific DNA binding domain. In this study, we will engineer vSET into a new gene transcriptional silencing technology and explore its great potential as a new epigenomics tool through characterizing vSET activity in controlling transcriptional repression of Polycomb target genes, and studying epigenetic functions of the Polycomb repressive complex proteins in cells.

Public Health Relevance

This study aims to develop new transformative tools and technologies to tackle the most challenging problems in the current genomic research particularly the epigenetic regulation of gene transcription. The outcome will empower the research community to better understand the fundamental molecular basis of human biology of health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM119189-02
Application #
9343018
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Carter, Anthony D
Project Start
2016-09-01
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$366,120
Indirect Cost
$150,120
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Zaware, Nilesh; Zhou, Ming-Ming (2017) Chemical modulators for epigenome reader domains as emerging epigenetic therapies for cancer and inflammation. Curr Opin Chem Biol 39:116-125
Aguilo, Francesca; Walsh, Martin J (2017) The N6-Methyladenosine RNA modification in pluripotency and reprogramming. Curr Opin Genet Dev 46:77-82