# Investigating the role of genome folding in transcriptional regulation

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $403,750

## Abstract

Project Summary
During transcription, enhancers need to contact gene promoters across large chromosome domains.
Chromosome folding can assist enhancer-promoter communication by bringing them close together inside the
nucleus. Mutations that alter genome folding underlie many human diseases, including developmental disorders
and some cancers. Yet, even after decades of research, we do not understand the causal links between
chromatin architecture and transcription regulation. Specifically, we do not understand why DNA looping can
correlate positively, negatively, or sometimes not at all with gene activity. To move beyond correlation to
causation, we need to better understand the molecular processes that couple genome folding and gene
regulation. The cohesin complex has emerged as a key player in DNA looping, because it can hold two chromatin
fibers together and extrude DNA loops as it translocates on DNA. Cohesin is loaded on chromatin by its co-factor
NIPBL. Cohesin then translocates until it is blocked at binding sites for the CTCF transcription factor. We recently
developed tools that allow controlling various aspects of cohesin loop extrusion by manipulating NIPBL and
CTCF in mouse embryonic stem cells. These tools provide a novel approach to investigate the relationship
between loop extrusion by cohesin and transcription. In this proposed study, we will determine how transcription
and loop extrusion are molecularly coupled and elucidate the mechanisms that explain why only some genes
rely on loop extrusion to function. We will also address how cohesin loop extrusion contributes to the functions
of CTCF during cell differentiation. In addition, we will identify novel pathways that regulate enhancer-promoter
communication by modulating loop extrusion. To achieve these goals, we will combine gene editing, epigenomic
assays, biochemical assays and novel epigenome engineering modalities with high-throughput reporter assays
in mouse embryonic stem cells and their differentiated derivatives. These investigations will substantially deepen
our understanding of how genome folding by cohesin proteins influences gene transcription. Completion of this
project will open new avenues to explore how these processes go awry in disease, a question our group is
interested to investigate in the future.

## Key facts

- **NIH application ID:** 10465200
- **Project number:** 5R35GM142792-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Elphege-Pierre Julien Nora
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2021-08-09 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465200

## Citation

> US National Institutes of Health, RePORTER application 10465200, Investigating the role of genome folding in transcriptional regulation (5R35GM142792-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465200. Licensed CC0.

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