The experiments described in this proposal are focused on understanding the mechanisms underlying the maintenance of stable heritable states of gene expression during development, as well as their developmentally programmed reversal. The Drosophila homeotic genes remain a preeminent source of new insights into these mechanisms. We focus on the Polycomb Group (PcG) and Trithorax Group (TrxG) proteins, which regulate chromatin states associated respectively with transcriptionally silent and active states through their chromatin modifying and remodeling enzyme activities. Their activities are now implicated in many biological processes, including genome-wide control of transcriptional programs, stem cell maintenance and differentiation, regeneration, longevity and others. Disturbances in the function or regulation of PcG and TrxG proteins are now known suspected to underlie a wide variety of disease states from cancer, chronic inflammation, obesity, diabetes, metabolic syndrome and others, some of which appear to manifest heritable "transgenerational" effects.
The aims of proposed work are: 1) to further investigate a newly discovered activity of the TRX protein that will shed new light on its function in a maintaining active states and antagonizing Polycomb silencing;2) to investigate a new activity of the CBP protein which functionally integrates it even more intimately with TRX and suggests a mechanism by which TRX affects H3K27 acetylation by CBP to antagonize Polycomb silencing;3) to investigate a newly discovered role of the Polycomb protein (PC) in negatively modulating / antagonizing maintenance of active chromatin states. Understanding the role of these new factors in regulating Polycomb silencing will provide new insights into the mechanisms underlying the epigenetic inheritance of stable chromatin states during development.

Public Health Relevance

This proposal focuses on understanding the mechanisms underlying the epigenetic maintenance of stable states of gene expression by the Polycomb Group (PcG) and Trithorax Group (TrxG) proteins as well as the mechanisms underlying switching between active and silent states. It explores the role of newly identified proteins and enzyme activities that interact with Polycomb Group and Trithorax Group proteins and play a role in regulating their antagonistic effects on transcriptionally active and silent chromatin stats. Polycomb Group and Trithorax Group Polycomb Group proteins silencing mechanisms have recently been implicated in an increasingly wide array of biological processes from maintenance and differentiation of pluripotent stem cells, regeneration, longevity and metabolism. Disturbances in the function or regulation of PcG and TrxG proteins and resulting disturbances in epigenetic regulation of chromatin states are known or suspected to underlie a wide variety of disease states from cancer, chronic inflammation, obesity, diabetes, metabolic syndrome and others, some of which appear to manifest heritable transgenerational effects. This research will lead to a deeper understanding of the fundamental mechanisms underlying epigenetic silencing and the mechanisms that regulate it. It will provide new insights into the maintenance of cell identities, genome reprogramming for differentiation, and have broad implications for cancer and stem cell biology.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM039255-23
Application #
8729582
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Carter, Anthony D
Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Tie, Feng; Banerjee, Rakhee; Saiakhova, Alina R et al. (2014) Trithorax monomethylates histone H3K4 and interacts directly with CBP to promote H3K27 acetylation and antagonize Polycomb silencing. Development 141:1129-39
Mason-Suares, Heather; Tie, Feng; Yan, Christopher M et al. (2013) Polycomb silencing of the Drosophila 4E-BP gene regulates imaginal disc cell growth. Dev Biol 380:111-24
Stepanik, Vincent A; Harte, Peter J (2012) A mutation in the E(Z) methyltransferase that increases trimethylation of histone H3 lysine 27 and causes inappropriate silencing of active Polycomb target genes. Dev Biol 364:249-58
Tie, Feng; Banerjee, Rakhee; Conrad, Patricia A et al. (2012) Histone demethylase UTX and chromatin remodeler BRM bind directly to CBP and modulate acetylation of histone H3 lysine 27. Mol Cell Biol 32:2323-34
Tie, Feng; Banerjee, Rakhee; Stratton, Carl A et al. (2009) CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing. Development 136:3131-41
Kurzhals, Rebeccah L; Tie, Feng; Stratton, Carl A et al. (2008) Drosophila ESC-like can substitute for ESC and becomes required for Polycomb silencing if ESC is absent. Dev Biol 313:293-306
Tie, Feng; Stratton, Carl A; Kurzhals, Rebeccah L et al. (2007) The N terminus of Drosophila ESC binds directly to histone H3 and is required for E(Z)-dependent trimethylation of H3 lysine 27. Mol Cell Biol 27:2014-26
Tie, Feng; Siebold, Alex P; Harte, Peter J (2005) The N-terminus of Drosophila ESC mediates its phosphorylation and dimerization. Biochem Biophys Res Commun 332:622-32
Furuyama, Takehito; Banerjee, Rakhee; Breen, Thomas R et al. (2004) SIR2 is required for polycomb silencing and is associated with an E(Z) histone methyltransferase complex. Curr Biol 14:1812-21
Furuyama, Takehito; Tie, Feng; Harte, Peter J (2003) Polycomb group proteins ESC and E(Z) are present in multiple distinct complexes that undergo dynamic changes during development. Genesis 35:114-24

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