# Molecular analysis of ASH1L

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $1

## Abstract

Project Summary
Human ASH1L (absent, small, or homeotic discs like 1) mediates proliferation and survival of
hematopoietic stem cells and is often upregulated in leukemias. It is required for hematopoietic
development and expression of developmental genes, including the HOX gene family.
Upregulated activity of ASH1L, found in mixed lineage leukemia (MLL)-rearranged acute
lymphoblastic leukemia (ALL), is generally associated with a poor prognosis. ASH1L is a major
methyltransferase that methylates histone H3, generating the epigenetic mark H3K36me2
associated with transcriptional activation and elongation. ASH1L contains a unique combination
of the catalytic methyltransferase SET domain and adjacent bromodomain (BD), a PHD finger,
and a BAH domain with unclear biological roles. Our recent studies reveal that the BD, PHD and
BAH domains of ASH1L are epigenetic readers capable of recognizing distinctive states of histone
H3. The molecular mechanisms underlying these novel functions of ASH1L are unknown and will
be elucidated in the proposed studies. We hypothesize that the concomitant recognition of distinct
histone states by the PHD, BD and BAH domains recruits or stabilizes ASH1L at promoters of
ASH1L target genes and is necessary for the catalytic activity of ASH1L and methylation of H3K36
at these genes. We seek to understand a crosstalk between the BD, PHD and BAH domains of
ASH1L and determine the molecular mechanism and functional significance of the multivalent
engagement of ASH1L with chromatin. We will employ complementary in vitro and in vivo
approaches to establish the molecular and structural basis and define the biological importance
of histone binding by ASH1L readers. This research will provide atomic-resolution insights into
ASH1L signaling pathways that may constitute new targets for therapeutic interventions and
enhance our knowledge of fundamental principles underlying the epigenetic-driven gene
transcription. It will also lead to a better understanding of human cancers associated with aberrant
activity of ASH1L, including acute leukemias.

## Key facts

- **NIH application ID:** 10202533
- **Project number:** 5R01CA252707-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** TATIANA G KUTATELADZE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2020-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10202533

## Citation

> US National Institutes of Health, RePORTER application 10202533, Molecular analysis of ASH1L (5R01CA252707-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10202533. Licensed CC0.

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