# Regulation of chromatin dynamics

> **NIH NIH R35** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $972,930

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Peterson, Craig, Lewis
The overall objective of our research is to determine how chromosome structure influences gene
transcription, DNA replication and repair, with special emphasis on identifying and characterizing the chromatin
remodeling machines that control chromosome dynamics. Notably, genetic experiments have revealed ATP-
dependent chromatin remodeling enzymes as essential regulators of virtually every chromosomal process, and
their dysregulation leads to a variety of diseases, including cancer. Our research efforts can be organized
into three inter-related areas: (1) Mechanistic studies of ATP-dependent chromatin remodeling enzymes,
focusing primarily on the structure and function of the 14-subunit, SWR1C remodeler; (2) Investigating roles for
the INO80C remodeler in DNA replication and the maintenance of genome stability; and (3) Probing how the
expression of newly replicated genes is repressed following replication fork passage, a process termed
transcriptional buffering. The SWR1C remodeling enzyme catalyzes a novel, ATP-dependent histone
exchange event that controls the deposition of the H2A.Z histone variant within nucleosomes that flank
promoters of genes transcribed by RNA polymerase II, as well as nucleosomes that flank centromeres and
replication origins. Mammalian homologs of SWR1C and INO80C, including the p400/Tip60 and hINO80
complexes, are key for proper stem cell function, genome stability, development, and gene expression. How
SWR1C catalyzes ATP-dependent deposition of H2A.Z remains largely unknown, and our proposed
mechanistic studies will include ensemble and single molecule fluorescence-based assays to define steps of
the histone dimer exchange reaction, as well as a combination of mass spectrometry and cryoEM methods to
probe how SWR1C distinguishes different nucleosomal substrates.
Studies from us and others have demonstrated that chromatin dynamics play a large role in regulating
transcription of both coding and noncoding RNAs, and disruption of this balance can impact genomic stability.
In particular, our work on INO80C has found that it prevents pervasive noncoding transcription from impinging
on replisome function in both yeast and mammalian cells. We propose a variety of genomic methods to probe
key unanswered questions: How does INO80C block noncoding transcription? How does transcription impact
fork structure? Does INO80C collaborate with the conserved forkhead transcription factors to organize origins
into a nuclear compartment? Our in vivo studies will extend to transcriptional regulation during S phase. We
have used Nascent transcript sequencing to confirm that newly replicated genes are transiently repressed 2-
fold until the subsequent G2 phase. Termed “transcriptional buffering” this process is conserved in mammals
and is believed to prevent transient aneuploid states during S phase. How buffering is established and
removed is not known, an...

## Key facts

- **NIH application ID:** 10833705
- **Project number:** 5R35GM122519-08
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Craig L Peterson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $972,930
- **Award type:** 5
- **Project period:** 2017-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833705

## Citation

> US National Institutes of Health, RePORTER application 10833705, Regulation of chromatin dynamics (5R35GM122519-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10833705. Licensed CC0.

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