# Transcription regulation in chromatin

> **NIH NIH R35** · STOWERS INSTITUTE FOR MEDICAL RESEARCH · 2024 · $424,877

## Abstract

Project Summary
The goals of this proposal are to investigate fundamental mechanisms of chromatin modifiers
which, when perturbed, may create conditions that can lead to cancer and other diseases in
humans. These studies will largely focus on chromatin remodeling complexes (e.g. Swi/Snf) and
proteins which modify histones (e.g. methylation, phosphorylation) in response to transcription,
cell signaling and metabolism. The Swi/Snf nucleosome-remodeling complex functions as a
tumor suppressor. Recurrent mutations in Swi/Snf are found in many cancers. This proposal
focuses on novel functions of Swi/Snf complexes in yeast and mammalian cells that may
contribute to cancer development when lost. Many subunits of the mammalian Swi/Snf complex
have alternative paralog subunits which occupy different versions. Importantly, depletion of
multiple paralogs of specific subunits has been shown to be synthetic lethal in cancer cell lines
suggesting potential therapeutic avenues. We will investigate the redundant and nonredundant
functions of paralogous subunits starting with ARID1A/ARID1B and SMARCA2/SMARCA4
(alternative ATPase subunits). We have found that ARID1B (but not ARID1A) interacts with
paraspeckle (ribonucleoprotein particle) components and regulates splicing. We will explore the
mechanisms and functions of Swi/Snf interactions with paraspeckles. We have discovered that
SMARCA2 bromodomain undergoes acetylation unlike its paralog SMARCA4. We will
investigate how this modification affects the activities of SMARCA2-containing Swi/Snf
complexes including their interactions with acetylated nucleosomes. In yeast we have found that
Swi/Snf regulates a number of genes involved in sulfur amino acid metabolism (The MET
regulon). We will investigate the role of Swi/Snf in controlling the transcription factor Met4 and
the MET regulon in general which is of particular interest due to the role of Met4 and the MET
regulon in regulating cellular processes such as redox homeostasis, methylation, phospholipid
metabolism, protein synthesis and cell cycle progression. Our discovery that the mammalian
SETD2 methyltransferase interacts with RNA processing proteins (e.g. hnRNPL) has led us to
investigate how these interactions regulate histone methylation during transcription and RNA
splicing and processing. Finally, in yeast we discovered a nutrient sensing signaling pathway
combining the CK2 and AMPK pathways to converge on the Tda1 kinase which phosphorylates
histone H3T11 and activates stress responsive genes. Proposed studies will investigate
regulation of Tda1, the functions of H3T11 phosphorylation in gene activation and whether this
nutrient sensing pathway is conserved in mammals.

## Key facts

- **NIH application ID:** 10752713
- **Project number:** 5R35GM118068-08
- **Recipient organization:** STOWERS INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** JERRY L WORKMAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $424,877
- **Award type:** 5
- **Project period:** 2016-05-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752713

## Citation

> US National Institutes of Health, RePORTER application 10752713, Transcription regulation in chromatin (5R35GM118068-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10752713. Licensed CC0.

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