# Deciphering enhancer regulation in stem cells

> **NIH NIH R35** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $402,500

## Abstract

Project Summary
The hallmark of pluripotent stem cells (PSCs) is their capability to self-renew and differentiate, which is governed
by the core pluripotency circuitry consisting of pluripotency factors OCT4, SOX2, and NANOG. Enhancers are
fundamental in regulating the spatial and temporal expression of pluripotency genes and lineage specific genes
during cellular differentiation and embryogenesis. Enhancer-regulating epigenetic modifiers play critical roles in
normal physiological processes and human pathogenesis. Epigenetic marks such as H3K4me1 and H3K27ac
are widely believed to regulate the activity and higher-order chromatin structure of enhancers by directly
remodeling local chromatin and/or recruiting reader proteins. However, recent discoveries of catalytic-
independent functions of multiple histone modifiers suggest that these enzymes govern enhancers and stem cell
differentiation via a non-catalytic manner. Despite the importance of epigenetic modifiers in mammalian
development and human diseases, how they sustain stem cell identity and impact human health is poorly
understood. I previously demonstrated that while enhancer activation does not require the catalytic activity of
histone methyltransferase MLL4 in PSCs, it is regulated by the functional antagonism between MLL4 and histone
demethylase LSD1. Using state-of-the-art unbiased approaches, my lab recently unveiled novel mechanisms
underlying the role of enhancer-regulating epigenetic modifiers in PSCs, providing insight into elucidating gene
regulation and cell fate transition. Here, I propose to build two research areas in my laboratory focused on
enhancer-regulating epigenetic modifiers. The first research area will focus on identifying catalytic-independent
functions of LSD1 in governing gene expression and cellular differentiation. The second research area will focus
on determining how MLL4 and its interactors modulate enhancer activity and cell fate transition. I anticipate that
accomplishing the proposed studies will reveal novel mechanisms underlying enhancer regulation, decipher how
stem cell self-renewal and differentiation are governed, and pave the way for understanding the pathogenesis of
diseases driven by enhancer malfunction.

## Key facts

- **NIH application ID:** 10915574
- **Project number:** 5R35GM150668-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Kaixiang Cao
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915574

## Citation

> US National Institutes of Health, RePORTER application 10915574, Deciphering enhancer regulation in stem cells (5R35GM150668-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10915574. Licensed CC0.

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