# Chromatin Dynamics and Genome Regulation

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $405,000

## Abstract

Dynamic regulation of chromatin during mammalian development allows the specification of
over 200 different cell types from a single genome. In addition to post-translational modification
of histone proteins, selective incorporation of histone variants into chromatin adds to the
complexity of epigenetic regulation. For example, histone variant H3.3 differs from canonical H3
by only 4-5 amino acids, yet displays distinct genomic and developmental enrichment
properties. While long associated with gene activation, recent studies suggest that H3.3 has
multiple functions in distinct genomic regions that are not always correlated with an active
chromatin state. The identification of mutations in H3.3 and associated proteins in human
cancers, including pediatric glioblastomas and pancreatic neuroendocrine tumors, has
heightened the pressing need to understand the role of this histone variant in a developmental
context. Despite increased interest, how H3.3 contributes uniquely to the function of chromatin
is a long-standing, unanswered question in the field. We propose an innovative program
combining mouse genetics, biochemistry, chemical biology, and cutting-edge genomics to
understand the functional relevance of H3.3-mediated chromatin dynamics. Our central
hypothesis is that H3.3 deposition promotes the establishment of unique developmentally
regulated chromatin landscapes that allow appropriate cell fate decisions to be made. Our
preliminary data suggests that nucleosome turnover rates are reduced in the absence of H3.3,
and that H3.3 dynamics may facilitate histone post-translational modification states at specific
genomic regions. Over the course of our studies we will (1) define the mechanisms underlying
H3.3 function in promoting specific histone post-translational modification states, (2) identify
regulatory mechanisms that control deposition of H3.3 at specific genomic loci, and the
distribution of the histone variant between the two known chaperone systems, and (3) determine
the importance of chromatin dynamics in the ability of lineage-specific transcription factors to
bind target regulatory elements during cell fate transitions in the early embryo. Our proposed
research is significant because it will establish chromatin variants as necessary components of
cell fate transitions, and serve as a platform to understand epigenetic regulation of cell identity
in both homeostasis, but also developmental misregulation and disease states.

## Key facts

- **NIH application ID:** 9973224
- **Project number:** 5R35GM124958-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Laura Banaszynski
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2017-08-04 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973224

## Citation

> US National Institutes of Health, RePORTER application 9973224, Chromatin Dynamics and Genome Regulation (5R35GM124958-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973224. Licensed CC0.

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