# Exploring novel regulatory mechanisms underlying enhancer activation and cell fate transition

> **NIH NIH K99** · NORTHWESTERN UNIVERSITY · 2020 · $101,557

## Abstract

Project Summary/Abstract
Misregulation of enhancer activity leads to various developmental disorders including thalassemia, Cornelia de
Lange syndrome, and Kabuki syndrome. The major enhancer regulator Mll4 belongs to the family of the Su(var)3-
9, Enhancer-of-zeste, Trithorax (SET) domain containing histone methyltransferases named COMplex of
Proteins ASsociated with Set1 (COMPASS), which places methylation marks at lysine 4 of histone H3 (H3K4).
Mll4 is essential for mammalian development and its heterozygous loss-of-function mutations lead to various
human diseases including Kabuki syndrome and cancer. I recently demonstrated that Mll4 is the major enzyme
depositing mono-methylation at H3K4 (H3K4me1), an enhancer-decorating epigenetic mark whose function
remains elusive. Moreover, I have defined catalytic activity dependent and independent functions of Mll4 in
enhancer modulation and stem cell differentiation, and have unveiled an antagonism between enhancer-binding
epigenetic machineries in transcriptional control that could underlie the developmental consequences of the
heterozygous loss-of-function mutations of Mll4 in human disease. Based on these findings, I hypothesize that
Mll4 cooperates with key transcription factors and epigenetic modifiers to modulate enhancer activity, chromatin
structure, and transcriptional outputs during stem cell maintenance and differentiation. The studies proposed
here aim to elucidate the molecular mechanisms of enhancer regulation, and to provide insights for developing
novel therapies targeting diseases driven by the loss of function of epigenetic modifiers. Specifically, the outlined
research will 1) elucidate how epigenetic marks impact enhancer functions and cell fate transition; 2) determine
the role of higher order chromatin structure in stem cell maintenance and differentiation; 3) identify novel factors
and pathways involved in modulating enhancer activity and determining cell fate. To achieve the long-term career
goal of defining the epigenetic mechanisms underlying mammalian development and disease, I will acquire
training in biochemistry, proteomics, bioinformatics, stem cell biology, and genome-wide screening during the
mentored phase of this application. Moreover, I will participate in grant writing workshops and career
development courses to strengthen my skills in writing and leadership. With the acquired training, I will be well-
prepared for the task of delineating the machineries and mechanisms in modulating gene expression, chromatin
structure, and cell fate determination in the independent R00 phase. In summary, the K99/R00 award, together
with the experiences that I have garnered as a graduate student and postdoc, the guidance from the mentors
and collaborators, and the superb research environment at Northwestern University's Feinberg School of
Medicine, will ensure a successful transition for me to continue my independent scientific career in the field of
stem cell biology and epigenet...

## Key facts

- **NIH application ID:** 9891069
- **Project number:** 5K99HD094906-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Kaixiang Cao
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $101,557
- **Award type:** 5
- **Project period:** 2019-03-11 → 2020-09-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891069

## Citation

> US National Institutes of Health, RePORTER application 9891069, Exploring novel regulatory mechanisms underlying enhancer activation and cell fate transition (5K99HD094906-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9891069. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*