# Understanding the Role of Histone Ubiquitination in Plasticity and Neurodevelopmental Disease

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2024 · $34,623

## Abstract

Project Summary
Human genetic studies have linked autism and related neurodevelopmental disorders (NDDs) to disruption of
genes encoding epigenetic factors, but a significant number remain poorly understood. Defining the functions of
these genes and their associated epigenetic pathways in the brain will provide insights into the molecular
pathology underlying brain dysfunction. An epigenetic modification with emerging connections to NDD mutation
is histone H2B ubiquitination (H2Bub), a chromatin mark involved in gene regulation. Mutation of the adapter
protein necessary for recruitment of H2Bub deposition factors to chromatin, WW domain containing adapter with
coiled coil (WAC), is causative to the recently described NDD known as DeSanto-Shinawi Syndrome (DESSH).
Although the pathology of DESSH is primarily neurological, the role of WAC and H2Bub in the brain remains
entirely unstudied. Recent evidence outside the nervous system suggests a role for H2Bub in regulating inducible
transcription, specifically the shut-off following induction. This may be particularly relevant to the brain, as tuning
of neural connectivity during development and plasticity in neurons requires precise control of the activity-
induced gene expression program. Upon depolarization, this suite of genes is rapidly transcribed then silenced
to provide a burst of synaptic regulatory proteins that facilitate circuit development and plasticity. Our preliminary
studies have revealed dynamic changes in H2Bub at these response genes and a requirement for WAC
expression in their proper shut-off, the exact mechanism of this regulation remains unclear. This proposal will
determine the extent and molecular mechanism by which WAC and H2Bub regulate neuronal activity
dependent transcription and explore the functional consequences of their disruption in a DESSH model.
In Aim 1, an orthogonal depletion of H2Bub along with structural manipulation to WAC will be used to parse the
key function of WAC in H2Bub deposition and activity-dependent transcription in neurons. The molecular
mechanism will then be dissected through integration of transcriptional and epigenetic disruption upon a loss of
WAC in neurons. This will define the mechanism by which WAC functions in activity-dependent transcription and
establish H2Bub as a novel regulator of this pathway. Aim 2 will investigate the molecular and functional
consequences of a DESSH-relevant heterozygous loss of WAC in murine learning and memory, which is well
established to depend on activity-dependent programs. This analysis will begin to uncover molecular drivers of
neurocognitive phenotypes such as intellectual disability observed in DESSH. Overall, these studies will define
a novel function of WAC and H2Bub in neurons and provide insight into how their disruption can drive
neurodevelopmental disease.

## Key facts

- **NIH application ID:** 10995404
- **Project number:** 1F31NS139506-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Alyssa A Erickson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,623
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995404

## Citation

> US National Institutes of Health, RePORTER application 10995404, Understanding the Role of Histone Ubiquitination in Plasticity and Neurodevelopmental Disease (1F31NS139506-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10995404. Licensed CC0.

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