# Control and function of repressive chromatin domains

> **NIH NIH R35** · UNIVERSITY OF GEORGIA · 2024 · $393,512

## Abstract

Project Summary/Abstract
The long-term goals of this project are to understand the composition, assembly, and function of specialized
chromatin domains. Polycomb Group (PcG) proteins interact to form enzyme complexes that modify
chromatin and assemble repressed chromatin states in animals, plants, and some fungi. Polycomb
Repressive Complex 2 (PRC2) is a highly conserved histone methyltransferase complex that is essential for
multicellular development and plays key roles in maintenance of stem cell identify, X-chromosome
inactivation, and gene regulation. Mutations that alter PRC2 function are responsible for human Weaver
syndrome and multiple cancers. Despite the importance of PcG proteins in human health and nearly 80
years of investigation, important mechanistic details regarding the establishment and epigenetic inheritance
of PcG repressed chromatin remain unknown. Our studies with the model fungus Neurospora crassa have
begun to address these critical gaps in knowledge. N. crassa is a powerful experimental system that shares
key features of the PcG system with higher eukaryotes. Importantly, components of PRC2 are structurally
and functionally conserved, in contrast to major yeast models Saccharomyces cerevisiae and
Schizosaccharomyces pombe. Our recent efforts have uncovered new genes required for PcG repression
and have begun to generate mechanistic insights into their functions. We will apply hypothesis-driven
genetic, molecular, proteomic, and genomic approaches to define functions of newly identified genes, and
we will perform discovery-driven genetic screens to identify new regulators and components of Polycomb
repressed chromatin domains. Major questions will be addressed during the grant period include. 1) What
are the mechanisms that control de novo establishment, spreading, and epigenetic inheritance of
H3K27me3? 2) How does ISWI, a nucleosome sliding ATP-dependent chromatin remodeling enzyme
control to assembly and maintenance of PcG repressed domains? 3) How are H3K27me3 levels re-
established following DNA replication? 4) What other factors control and comprise PcG-repressed chromatin
domains? Successful completion of the proposed aims will uncover general principles and mechanisms
governing assembly and function of PcG-repressed chromatin domains. Findings from these studies will
serve as a framework for future studies in higher eukaryotes, including humans. In addition, because PcG
proteins are linked to cancer and other genetic diseases, understanding the regulation and function of these
key chromatin regulators will ultimately improve diagnosis and treatment of human disease.

## Key facts

- **NIH application ID:** 10764644
- **Project number:** 1R35GM152134-01
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Zachary Lewis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $393,512
- **Award type:** 1
- **Project period:** 2024-07-12 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764644

## Citation

> US National Institutes of Health, RePORTER application 10764644, Control and function of repressive chromatin domains (1R35GM152134-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10764644. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*