# Deciphering the Stepwise Regulatory Mechanisms of Genome Folding

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $388,750

## Abstract

Deciphering the Stepwise Regulatory Mechanisms of Genome Folding
In multicellular organisms, the precise regulation of gene expression across the different cell types and
developmental stages is achieved through the orchestration of cis-regulatory elements, notably enhancers.
These elements are positioned distantly from gene promoters and exert their function by establishing physical
interactions with them. Crucially, these interactions depend on the three-dimensional folding of the genome. Any
disruptions to this highly orchestrated genome folding, which can give rise to dysregulated gene expression,
have been implicated in the pathogenesis of a myriad of diseases, including cancer and developmental
disorders. Hence, unraveling the mechanisms that govern genome folding becomes a paramount endeavor in
order to gain a comprehensive understanding of the precise control of gene expression, both in healthy
physiological contexts and in the aberrant states associated with disease. Over the last two decades, significant
advancements in genomic studies employing proximity-ligation and sequencing techniques have revealed the
cohesin complex as a key driver of genome folding. Recent groundbreaking single-molecule imaging
experiments have demonstrated cohesin's motor activity, directly engaging in loop extrusion to fold linear DNA
in vitro. However, it has been largely elusive how cohesin-mediated genome folding is regulated in the living
cells. To answer this question, we will focus on three research topics: 1. How do nuclear bodies influence cohesin
function? 2. What are the post-translational modifications (PTMs) on cohesin-associated factors and their impact
on genome folding? 3. What are the cytosolic signals that regulate genome folding through cohesin and how do
they do so? Cohesin-mediated genome folding is achieved through highly dynamic processes of cohesin
loading/loop extrusion, extrusion stalling, and cohesin unloading. We will dissect and pinpoint the specific
process within the genome folding that are regulated by nuclear bodies, PTMs and cytosolic signals. Collectively,
our proposed studies aim to unveil novel molecular mechanisms governing genome folding, providing a
comprehensive understanding of how genome folding is regulated in living cells and its contribution to disease
states.

## Key facts

- **NIH application ID:** 10940618
- **Project number:** 1R35GM155096-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Wonho Kim
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940618

## Citation

> US National Institutes of Health, RePORTER application 10940618, Deciphering the Stepwise Regulatory Mechanisms of Genome Folding (1R35GM155096-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10940618. Licensed CC0.

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