# Investigating SMARCE1 in Regulating Cohesin Activity, Chromatin Folding, and Gene Expression

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $48,974

## Abstract

PROJECT SUMMARY
 The cohesin complex mediates the hierarchical organization of the genome into chromatin loops and
topologically associating domains (TADs) through a proposed model of loop extrusion. Indeed, cohesin plays an
important role in human health, since mutations in cohesin cause a developmental disorder known as Cornelia
de Lange Syndrome (CdLS). However, mechanistically, it remains unclear how cohesin dysfunction contributes
to the pathogenesis of CdLS. Interestingly, ~30% of CdLS patients do not harbor mutations in known cohesin
components highlighting the gap in our understanding of cohesin regulation. Therefore, we reason that unknown
factors are contributing to cohesin function, and that uncovering these factors may reveal mechanistic links
between cohesin dysfunction and disease. To this end, we completed screening genome-wide for genes that
can modulate chromatin interactions across TADs. We found that SMARCE1, which is a DNA-binding subunit of
the ATP-dependent human chromatin remodeling complex SWI/SNF, promotes inter-TAD interactions, which
cohesin also facilitates. We next determined that SMARCE1 genetically interacts with cohesin, suggesting
SMARCE1 regulates cohesin-mediated chromatin looping. Strikingly, mutations in SWI/SNF cause Coffin-Siris
Syndrome (CSS), a developmental disorder that shares overwhelming phenotypic overlap with CdLS. The goal
of this proposal is to determine how SMARCE1 regulates cohesin and chromatin looping across the
genome, and the extent to which a cohesin dysfunction may underlie a shared signature of gene
misexpression in CdLS and CSS through two related, but independent aims.
 I will first determine the SWI/SNF dependency of SMARCE1 in promoting cohesin-mediated loop
extrusion. Next, I will interrogate the consequences of SWI/SNF and SMARCE1 loss on global cohesin
localization and chromatin organization. In parallel, I will intersect the changes in chromatin folding following
SMARCE1 depletion with changes in SWI/SNF and cohesin localization. Taking advantage of publicly available
genomic datasets, I will also intersect any detected differential looping or cohesin localization in the context of
different chromatin states. Furthermore, the novel role of a CSS-associated gene in chromatin folding suggests
that CdLS and CSS may converge on cohesin dysfunction. In addition to the overlapping clinical presentations
of CdLS and CSS, I will define the extent to which CdLS and CSS share signatures of cohesin dysfunction
in patient-derived cell lines. I will investigate whether chromatin is misfolded in CSS as in CdLS and how this
chromatin misfolding correlates with comparative transcriptomics between CSS and CdLS. As is the case in
CdLS, I will determine if any marker of cohesin dysfunction correlates with CSS disease severity. Completion of
this proposal will define the role of SMARCE1 in regulating cohesin-mediated chromatin folding and highlight a
potential shared molecular etiology at the intersec...

## Key facts

- **NIH application ID:** 10996033
- **Project number:** 1F31HD114273-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** May Wai
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-16 → 2027-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996033

## Citation

> US National Institutes of Health, RePORTER application 10996033, Investigating SMARCE1 in Regulating Cohesin Activity, Chromatin Folding, and Gene Expression (1F31HD114273-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10996033. Licensed CC0.

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