# Chromatin Mechanisms of Neuronal Maturation

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $430,544

## Abstract

Neuronal differentiation requires the precise orchestration of gene expression programs. Temporal control of
transcription is particularly important in maturing postmitotic neurons of the postnatal brain because these cells
need to express gene products that refine neuronal function and circuitry during specific critical periods of brain
development. Epigenetic regulation of chromatin structure is known to play a role in establishing cell-type
specific programs of gene expression during early stages of cell fate determination, but the chromatin
mechanisms that regulate gene expression during terminal phases of differentiation remain to be fully
understood. The goal of this proposal is to identify chromatin mechanisms that coordinate the induction of
genes in maturing neurons of the CNS. To discover these chromatin mechanisms of neuronal differentiation,
and to determine how these mechanisms are regulated across multiple stages of neuronal maturation, we
have characterized chromatin accessibility, enhancer activation, and gene expression in differentiating
cerebellar granule neurons (CGNs) of the postnatal mouse in vivo. We have observed that thousands of
regulatory elements show chromatin accessibility changes as CGNs differentiate, and we have verified that
many of these differentially accessible regions function as developmental stage-specific enhancers of neuronal
genes. Furthermore our data identify a specific group of the genes selectively expressed in mature CGNs of
the cerebellum that are associated with repressive histone H3 lysine 27 trimethylation (H3K27me3) at early
postmitotic stages of CGN differentiation yet lose this mark as CGNs mature. Consistent with a role for active
histone demethylation in the induction of these genes, we find that at least a subset of these genes show
increased H3K27me3 and reduced mRNA expression in CGNs lacking the H3K27 demethylase Kdm6b. The
overarching hypothesis of this proposal is that the molecular regulators of H3K27me3 dynamics in
postmitotic neurons play a key role in timing neuronal maturation. To address this hypothesis we propose the
following Specific Aims: 1) To characterize the dynamic demethylation of H3K27 in postmitotic neurons
maturing in vivo, 2) To determine the role of the H3K27 demethylase Kdm6b in neuronal maturation, and 3) To
identify enhancer mechanisms of transcriptional derepression in maturing neurons. Together these studies will
identify the molecular mechanisms that mediate the gene-specific loss of H3K27me3 in maturing CGNs, and
they will directly test the importance of the developmental derepression of H3K27me3-silenced genes for
functional neuronal maturation.

## Key facts

- **NIH application ID:** 10159321
- **Project number:** 5R01NS098804-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Anne Elizabeth West
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $430,544
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159321

## Citation

> US National Institutes of Health, RePORTER application 10159321, Chromatin Mechanisms of Neuronal Maturation (5R01NS098804-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10159321. Licensed CC0.

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