# Functional Analysis of Epigenetic Complexes

> **NIH NIH R35** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $876,759

## Abstract

Abstract: For humans to develop properly, the fertilized egg must divide in a manner that
generates a body that has the correct organs and appendages in the correct places. Much of this
is determined by the proper temporal and spatial regulation of master regulatory genes that
guide formation of the differentiated cells that make up organs and appendages. A key aspect
of this developmental process is the ability to maintain master regulatory genes in a repressed
state in cells where their expression might cause inappropriate cell behavior. Mis-expression of
even a single master regulatory gene, such as those encoded in the HOX loci, can result in a cell
behaving in a manner incompatible with its body location and tissue type. The Polycomb-
Group (PcG) group of genes is largely responsible for maintaining this repression, based upon
intensive study over the past 70 years. Maintaining active expression patterns for genes is
equally critical for development. A set of genes that maintains activation, called the trithorax-
Group (trxG), was isolated via their ability to suppress PcG mutations. This application
describes the continuation of our work on understanding the function of the proteins encoded
by the PcG and trxG genes. These proteins form several complexes. The PcG complexes PRC1
and PRC2 are each large complexes that contain several PcG gene products. PRC1 is the main
`engine' of repression in the Polycomb-Group and is known to interact with chromatin, the
structure that packages genes in the nucleus of cells. Chromatin structure can render the
enclosed DNA inaccessible to activating factors. A prominent hypothesis is that repression can
be generated by generating highly packaged DNA that is no longer able to be transcribed and
expressed. We describe approaches to investigate the various mechanisms used by PRC1 to
generate packaged chromatin. PRC1 works together with PRC2 to generate repression. PRC2
methylates nucleosomes, the primary packaging unit of chromatin, on residue H3K27, a topic of
intensive study in numerous laboratories and companies. We intend to provide novel
information by exploring repressive activities of PRC2 that are unrelated to methylation. We
will also characterize methylation by PRC2 of a separate protein involved in gene regulation,
ElonginA. Finally, we will characterize two separate nucleosome remodeling activities encoded
by trxG genes, the mammalian SWI/SNF (BAF) complex and mammalian CHD7. We will
explore interactions between SWI/SNF subunits and cohesin, a chromatin organizing activity,
and determine how those interactions impact long range interactions in chromatin. We will
examine the role for a lncRNA called HERVH in targeting CHD7 activity.

## Key facts

- **NIH application ID:** 10130558
- **Project number:** 5R35GM131743-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ROBERT KINGSTON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $876,759
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130558

## Citation

> US National Institutes of Health, RePORTER application 10130558, Functional Analysis of Epigenetic Complexes (5R35GM131743-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10130558. Licensed CC0.

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