# Molecular Basis of Drosophila Homeotic Gene Regulation

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $402,500

## Abstract

Abstract
The broad goals of this research are to understand the mechanisms that promote stable, mitotically heritable
states of gene expression during development. They continue to focus on characterizing the mutually
antagonistic chromatin-directed activities of Drosophila Polycomb Group and Trithorax Group proteins that
promote and maintain the distinct chromatin states associated with transcriptionally silent and active genes
respectively. Their activities are implicated in many biological processes, including cell fate determination, stem
cell maintenance and differentiation, regeneration, and others. They are implicated in human diseases, notably
various cancers. The proposed experiments build on discoveries made in the previous funding period. Aim 1 is
to investigate a newly discovered inhibitory activity of the Polycomb (PC) protein, a PRC1 subunit, on the
catalytic activity of the CBP acetyltransferase, a global transcriptional co-activator. We will use CRISPR
genome editing to create PC mutant proteins that fail to bind CBP in vitro and in vivo. We will characterize their
effects in vivo on expression of both silent and active Polycomb-regulated genes, as well as on their genome-
wide distribution. Aim 2 is to investigate the effects of newly discovered acetylation of PC on its in vivo function
using CRISPR genome editing and transgenic lines that express PC containing substitutions of acetylated
lysines with glutamines (acetyl-K mimic) and arginines (charge conservative but unacetylatable). Aim 3 is to
investigate the interplay of the chromatin-directed activities of TRX methyltransferase and CBP
acetyltransferase, extending our observation that the histone H3K4me1 product of TRX stimulates its
subsequent acetylation of H3K27 by CBP, which directly blocks repressive H3K27 methylation by PRC2. We
will determine if binding of CBP to TRX is required for this effect in vivo by mutating the CBP-binding region of
TRX. This work will provide new insights into the regulation of active and silent chromatin states during
development.
.

## Key facts

- **NIH application ID:** 10001063
- **Project number:** 5R01GM039255-27
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Peter J. Harte
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 1988-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001063

## Citation

> US National Institutes of Health, RePORTER application 10001063, Molecular Basis of Drosophila Homeotic Gene Regulation (5R01GM039255-27). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10001063. Licensed CC0.

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