# Role of UTX condensation in chromatin regulation

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $418,770

## Abstract

PROJECT ABSTRACT
UTX/KDM6A is an important tumor suppressor and developmental regulator, and is frequently
mutated in human cancers and certain neurodevelopmental disorders including Kabuki
syndrome. Though UTX is a histone H3K27 demethylase, the demethylase activity is often
dispensable in mediating tumor suppression and developmental regulation, and the key molecular
activity of UTX in these processes remains elusive. UTX is thought to regulate chromatin activity
by associating with and coordinating the function of MLL3/KMT2C and MLL4/KMT2D, the major
H3K4 mono-methylase at enhancers, and the p300 histone acetyltransferase, all of which are
also frequently mutated in human cancers. In our preliminary studies, we found that the tumor
suppressive activity of UTX requires its phase separation property conferred by its core
Intrinsically Disordered Region (cIDR). Endogenous UTX forms dynamic condensates in mouse
embryonic stem cells (ESCs) and its cIDR is important for ESC differentiation. UTX and MLL4
form co-condensates that enhance the H3K4 mono-methylation activity. We also found that UTY,
the Y chromosome homolog of UTX, has weaker tumor suppressive activity that is associated
with formation of less dynamic condensates. These results let us formulate our central hypothesis
that UTX needs to be in condensates with appropriate biophysical properties to be active in
regulating gene expression on chromatin in regulating tumorigenesis and stem cell differentiation.
We proposal two Specific Aims.
Aim 1. Determine the mechanisms by which UTX condensation regulates chromatin
activity. We will determine how UTX condensation regulates chromatin modification activities by
biochemical reconstitution, and also through integrative analyses of multiple levels of chromatin
activity in both transduced cancer cells and endogenous Utx-edited ESCs.
Aim 2. Determine how biophysical properties of the UTX condensates regulate its
biological activities. We will study biophysical properties of UTX WT and variant condensates
and its associated co-activators. We will determine impacts of condensate properties on biological
activities at different levels in in both transduced cancer cells and endogenous Utx-edited ESCs.
We will also examine effect of disease-associated missense mutations of UTX on condensate
properties.

## Key facts

- **NIH application ID:** 10365699
- **Project number:** 1R01CA259573-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Hao Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,770
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365699

## Citation

> US National Institutes of Health, RePORTER application 10365699, Role of UTX condensation in chromatin regulation (1R01CA259573-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10365699. Licensed CC0.

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