# Mechanistic Studies of Genome Folding

> **NIH NIH R35** · RESEARCH INST OF FOX CHASE CAN CTR · 2024 · $470,000

## Abstract

Project Summary
Overview: During interphase, the cohesin complex extrudes chromatin loops to mediate the formation of
chromatin domains and loops, which are elementary 3D structures of the human genome and guide enhancer-
promoter interactions. Disruption to these structures can lead to many diseases including cancer. Our research
has significantly advanced our understanding of how cohesin actively extrude native chromatin loops.
Specifically, we have achieved the following milestones: 1) Established a simple yet very powerful system
enabling mechanistic studies of loop extrusion in near-native nuclei under highly controlled manners. 2)
Uncovered that cohesin engages with chromatin in distinct ways dependent on the stages of loop extrusion. 3)
Discovered distinct biochemical and conformation states of cohesin during loop extrusion.
Goals: Our preliminary results revealed a correlation between cohesin’s biochemical states and its role in
genome folding, and also demonstrated the power of our semi-in vitro systems to study genome folding. We aim
to use this system to capture and analyze distinct states of cohesin during the highly dynamic loop extrusion
process. Our innovative approach also affords us the ability to analyze additional cohesin-dependent activities
such as transcription. We plan to address four major gaps in our understanding of genome folding and its
relevance in cancer. 1) how dose cohesin engage with chromatin? We will use synthetic variants of cohesin
and CTCF to probe the molecular connection between CTCF binding and cohesin-chromatin interactions. 2)
What changes occur in cohesin's composition and conformation during the loop extrusion process? We will
establish a novel analytic framework to systematically explore dynamic changes of cohesin and identify novel
regulators of cohesin. 3) how does cohesin interplay with transcription machinery? We will employ our methods
to analyze cohesin’s states during transcription and probe the interplay between genome folding and
transcription. 4) how do cancer-associated mutations within cohesin affect genome folding and functions.
Cohesin mutations are strongly associated with cancer, but their mechanisms of action remain largely unclear.
We will integrate our analyses with AlphaFold to construct a predictive model and assess the impact of clinically
relevant mutations within cohesin on genome folding and transcription.
Vision: Our innovative methodologies not only enable the functional analysis of cohesin's biochemical states
(subunit composition and conformation such as its ring-like structure) during highly dynamic activities like loop
extrusion and transcription, but also afford a comprehensive understanding of genome folding and regulation,
particularly in the context of cancer.

## Key facts

- **NIH application ID:** 10940479
- **Project number:** 1R35GM154879-01
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Yu Liu
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $470,000
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940479

## Citation

> US National Institutes of Health, RePORTER application 10940479, Mechanistic Studies of Genome Folding (1R35GM154879-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10940479. Licensed CC0.

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