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.
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.
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