# ASH1L mediated transcription networks in autism spectrum disorders

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $44,657

## Abstract

ABSTRACT
Genetic research in autism spectrum disorder (ASD) has led to the discovery of a growing list of highly
penetrant mutations in chromatin modifiers and transcription factors. This recent progress provides an
important opportunity to define the molecular mechanisms in ASD, as well as to identify targets for new
treatment strategies. However, given the large number of seemingly independent ASD risk factors, a major
challenge for ASD research is to establish convergent mechanisms that group apparently distinct genetic
etiologies. We identified a novel point of convergence between the histone-methyltransferase ASH1L, a major
ASD genetic risk factor, and a cluster of ASD high-risk genes (e.g. FOXP1, RIMS1, NRX1a). We also find that
ASH1L counteracts the activity of Polycomb repressor complex in neural development. Hence, our data
uncover a transcriptional and epigenetic node linked to cell and circuit dysfunction underlying ASD phenotypes.
However, the transcriptional programs modulated by ASH1L that lead to neuronal dysfunction are
understudied. Our central hypothesis is that ASH1L counteracts Polycomb activity to orchestrate
neuronal development by modulating transcriptional programs that control synaptic function and
neuronal morphogenesis. We will define how ASH1L regulates neuronal development and function. We will
use a multilevel, synergistic and translational approach that leverages human and mouse systems to
determine how ASH1L modulates neuronal programs relevant to ASD pathogenesis. We are positioned to
undertake this work, based on our robust preliminary data and combined expertise in cellular/molecular
neuroscience, bioinformatic, chromatin biology and electrophysiology. 1) Determine how mutations in ASH1L
disrupt neuronal arborization and function in human stem cell experimental systems, 2) Define functional and
circuit phenotypes associated with ASH1L in rodent systems. 3) Define bulk and cell type specific epigenetic
and transcriptional signatures associated with ASH1L mutations that cause disease in mouse and human
neurons. Finally, we will define rescue strategies for the cellular, molecular, and electrophysiological
phenotypes observed in both mouse and human experimental systems.

## Key facts

- **NIH application ID:** 10990076
- **Project number:** 3R01MH127081-03S1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Judy Shih-Hwa Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,657
- **Award type:** 3
- **Project period:** 2023-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990076

## Citation

> US National Institutes of Health, RePORTER application 10990076, ASH1L mediated transcription networks in autism spectrum disorders (3R01MH127081-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10990076. Licensed CC0.

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