# Chromatin dysregulation in neurodevelopmental disorders

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $514,063

## Abstract

PROJECT SUMMARY
Chromatin-associated proteins are a major class of genes mutated in autism spectrum disorder (ASD) and
intellectual disability (ID). These genetic data indicate the importance of gene regulation for brain development,
however a significant challenge for the field is to determine how disruptions of chromatin regulators may
converge on specific biological processes in developing neurons. To address this challenge, here we focus in
detail on the biochemical and cellular mechanisms by which ID-associated frameshift mutations in the linker
histone H1.4 result in impaired neuronal development. As a histone, H1.4 is a direct component of chromatin;
thus, studying how mutations in this gene impair neural development offers the opportunity to gain specific
biochemical insight into mechanisms of chromatin regulation in neurons. Rahman Syndrome (RMNS) is a rare,
genetic form of ID caused by de novo heterozygous mutations in H1-4, which encodes histone H1.4. All
RMNS-associated mutations in H1-4 are small insertions or deletions that create a shared C-terminal
frameshift. Genetic data indicate that the mutant protein likely functions in a dominant negative or neomorphic
manner to lead to RMNS phenotypes, but the biochemical and cellular consequences of expressing RMNS
mutant histone H1.4 are poorly understood. We have found that expressing RMNS mutant histone H1.4 in rat
hippocampal neurons leads to the disruption of synaptic gene expression and neuronal firing. We hypothesize
that RMNS mutant H1.4 disrupts chromatin architecture in differentiating neurons to impair gene expression
programs that are required for synapse development and neuronal function. To determine how the RMNS
mutation of histone H1.4 leads to aberrant transcription and to evaluate the consequences for brain
development, we will use both biochemical and molecular genetic approaches in the developing mouse brain
and in human neurons. In Aim 1, we will build a foundation for these studies by using leading edge proteomic
and molecular genetic methods to characterize the expression, regulation, and chromatin distribution of histone
H1.4 over the course of neuronal differentiation in the mouse. To determine how RMNS mutations disrupt
synaptic gene expression in brain development, in Aim 2 we will use a novel in vivo protein tagging strategy to
identify proteins that interact with wildtype versus RMNS mutant H1.4. Finally, to determine how RMNS
mutations disrupt chromatin regulation, in Aim 3 we will study generate RMNS mutant H1.4 expressing iPSC-
derived neurons for biochemical histone H1 proteomics and gene expression analyses. We will then use a
novel method for low-input three-dimensional chromatin conformation capture to test the hypothesis that
RMNS mutant histone H1.4 disrupts higher level chromatin architecture. These studies will advance knowledge
of the causes of brain developmental abnormalities in RMNS, and they will contribute to understanding of the
specific mecha...

## Key facts

- **NIH application ID:** 10855114
- **Project number:** 1R01NS136375-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Anne Elizabeth West
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $514,063
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10855114

## Citation

> US National Institutes of Health, RePORTER application 10855114, Chromatin dysregulation in neurodevelopmental disorders (1R01NS136375-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10855114. Licensed CC0.

---

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