# The role of genome folding in regulating gene expression and chromatin state

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $105,800

## Abstract

PROJECT SUMMARY
Knowledge of how three-dimensional (3D) genome organization is linked to gene expression and chromatin
state is paramount to understanding human health and disease. The cohesin complex is a major regulator of
genome organization that dynamically extrudes DNA loops to bring together enhancers, promoters, and
insulators. While the insulator protein CTCF is known to capture and stabilize an extruding cohesin complex, it
is not clear how cohesin is stabilized at enhancers and promoters that lack CTCF. Furthermore, the causal role
of cohesin-mediated loops in regulating gene expression is not understood. We recently discovered that
cohesin variant complexes, composed of either STAG1 or STAG2 subunits and either PDS5A or PDS5B
subunits, colocalize across the genome, yet have surprisingly distinct effects on gene expression. In this
proposed study, we will answer the next set of questions about cohesin biology. We hypothesize that cohesin
complexes at specific genomic sites have distinct biochemical properties and binding partners that mediate
effects on transcription and chromatin state defined by histone modifications. To test these hypotheses, we are
using an integrative approach that combines genetic, biochemical, genomic, and proteomic assays in
embryonic stem cells and differentiated cells following genome editing, protein depletion, acute degradation, or
inhibition with small molecules. These studies will 1) identify novel cohesin-interacting proteins using proteomic
approaches, 2) investigate the properties of cohesin complexes at different genomic sites and with different
binding partners, and 3) elucidate the role of cohesin-mediated DNA loops in regulation of transcription and
chromatin state at genomic sites lacking CTCF. The proposed multi-disciplinary approach leverages our
extensive experience in functional genomics and expands on our recent findings that demonstrated roles for
cohesin subunits and cohesin regulators in DNA loop formation and transcription. This will contribute to our
long-term goal of applying cutting-edge technologies to uncover the molecular mechanisms that define how 3D
genome organization influences chromatin state and transcriptional control to govern cell identity. Completion
of this project will fill critical gaps in knowledge about gene regulation that inform our understanding of human
developmental disorders and cancers linked to epigenetic defects.

## Key facts

- **NIH application ID:** 11036826
- **Project number:** 3R35GM152103-01S1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jill Dowen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $105,800
- **Award type:** 3
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11036826

## Citation

> US National Institutes of Health, RePORTER application 11036826, The role of genome folding in regulating gene expression and chromatin state (3R35GM152103-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11036826. Licensed CC0.

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