# Transcriptional repression by Polycomb Repressive Complex 2

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2022 · $349,254

## Abstract

Project Summary
The long-term goals of this project are to understand assembly of repressed chromatin states and to
elucidate mechanisms of gene repression in these specialized chromatin environments. Polycomb Group
(PcG) proteins interact to form enzyme complexes that modify chromatin and assemble repressed chromatin
states in animals, plants, and most fungi. Polycomb Repressive Complex 2 (PRC2) is a highly conserved
histone lysine-27 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 its
importance, we lack a clear understanding of the mechanisms that control PRC2 and repress transcription
of PRC2 target genes. Preliminary studies with the model fungus Neurospora crassa have begun to address
these critical gaps in knowledge. Neurospora is a powerful experimental system that shares key features
with higher eukaryotes. Namely, components of PRC2 are structurally and functionally conserved, while
they are lacking in both major yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe. A
targeted RNA-sequencing screen of over 400 N. crassa gene deletion strains that lack known or predicted
chromatin-associated or chromatin regulatory proteins uncovered new genes required for PcG repression
and are beginning to yield mechanistic insights into their functions. Application of genetic, molecular,
proteomic, and genomic approaches will capitalize on these novel findings, and bioinformatic analyses will
interrogate this unique RNA-seq data set to: 1) determine how a conserved ATP-dependent chromatin
remodeling enzyme controls PRC2 and gene repression at PcG-repressed domains, 2) define mechanisms
by which constitutive heterochromatin components regulate PRC2, and 3) define a comprehensive PcG
chromatin network in a simple model system. Successful completion of the proposed aims will uncover
general principles and mechanisms governing assembly and function of PcG-repressed chromatin domains.
Because the first two newly identified components of PcG-mediated silencing are conserved, findings from
the proposed 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:** 10390294
- **Project number:** 5R01GM132644-04
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Zachary Lewis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,254
- **Award type:** 5
- **Project period:** 2019-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390294

## Citation

> US National Institutes of Health, RePORTER application 10390294, Transcriptional repression by Polycomb Repressive Complex 2 (5R01GM132644-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10390294. Licensed CC0.

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