# How does neuronal contact mediate astrocyte transcriptional maturation?

> **NIH NIH F31** · DUKE UNIVERSITY · 2024 · $41,865

## Abstract

ABSTRACT
Developing a healthy functioning brain depends on the coordination of neuronal circuit formation by glial cells
called astrocytes. Previous work has shown that astrocytes, born from the same neural stem cells after the end
of neurogenesis, require contact with neurons to mature morphologically, functionally, and transcriptionally.
Astrocytic expression of the cell adhesion molecule neuroligin 2 (Nlgn2) is necessary for neuronal contact-
dependent astrocyte morphogenesis and synaptogenesis. These findings led us to investigate how neuronal
contact mediates astrocyte morphogenesis and synaptogenic functions. To address this question, we performed
multiplexed indexed T7 chromatin immunoprecipitation (MintChIP) sequencing to measure histone modifications
across the astrocyte genome. These experiments found that the chromatin modification landscape changes
significantly over postnatal astrocyte development. Interestingly, when we measured histone modifications in
astrocytes from Nlgn2 KO mice, we found a substantial decrease in the H3K4me1 and H3K4me3 modifications
compared to wildtype astrocytes. Based on these preliminary findings, this proposal will test the hypothesis
that epigenetic histone modifications are the mechanistic link between neuronal contact and astrocyte
transcriptional maturation. Specifically, aim 1 will test how histone modifications and transcriptional maturation
change when astrocytes are cultured with or without neurons and whether inhibiting histone-modifying enzymes
is sufficient to prevent astrocyte transcriptional maturation. Aim 2 will investigate the molecular mechanisms of
Nlgn2-dependent astrocyte transcriptional maturation. In particular, we will test the hypothesis that the chromatin
remodeler Chd8 is required for Nlgn2-dependent H3K4 methylation and that preventing this H3K4 methylation
through astrocyte-specific Chd8 knockout will prevent astrocyte transcriptional maturation. The successful
completion of these aims will determine the extent to which histone modifications regulate astrocyte maturation
and further our understanding of the molecular mechanism responsible for Nlgn2-induced gene expression
changes in astrocytes. These findings will also be highly relevant to future work in neurodevelopmental disorders
as astrocyte-regulated synaptogenesis, and epigenetic regulation of gene expression are emerging as prominent
aspects of conditions like autism spectrum disorders. Finally, this project will provide an excellent training
experience for Mr. Justin Savage through its intersection of epigenetics and glial cell biology.

## Key facts

- **NIH application ID:** 10892070
- **Project number:** 5F31NS134252-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Justin Savage
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,865
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892070

## Citation

> US National Institutes of Health, RePORTER application 10892070, How does neuronal contact mediate astrocyte transcriptional maturation? (5F31NS134252-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10892070. Licensed CC0.

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