# Cell-type Specific Roles for H3 Serotonylation During Critical Periods of Postnatal Brain Development and Plasticity

> **NIH NIH F99** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $48,974

## Abstract

Project Summary/Abstract
The serotonergic (5HTergic) system is implicated in a wide range of neurodevelopmental and neuropsychiatric
phenomena, including regulation of mood and stress reactivity. While 5HT actions have been assumed to be
mediated exclusively through 5HT receptors, studies have established 5HT forms covalent bonds with histone
H3—resulting in H3 glutamine 5 serotonin (H3Q5ser)–a process known as H3 serotonylation. H3 serotonylation
plays key regulatory roles in establishing normal embryonic and adult patterns of brain transcriptional plasticity.
However, functional roles for H3 serotonylation during postnatal brain development, have been unexplored, and
the impact of environmental stimuli on this modification during early life remains unknown. Our laboratory
implemented FANS coupled CUT&RUN (C&R)-seq to profile the cell type-specific epigenomic landscape of H3
serotonylation in mouse medial prefrontal cortex (mPFC), across critical periods of postnatal brain development.
We identify cell-type-, sex-, developmental-, and early life stress- (ELS) induced alterations in H3 serotonylation
genomic enrichment, with males showing more pronounced developmental and ELS-induced changes in both
neuron and glia populations. In males, further analysis reveals, H3 serotonylation binding increases at
oligodendrocyte genes in response to ELS. While these findings are insightful, they alone cannot elucidate the
cell-type-specific functional roles of H3 serotonylation on gene expression or its potential influence on behavioral
phenotypes. In the F99 phase, I will test the hypothesis that H3 serotonylation critically regulates
neurodevelopmental gene expression, and perturbation by ELS results in altered gene expression and increased
vulnerability to stress-related behavioral phenotypes as a function of this novel PTM. I will utilize multi-omic
bioinformatic tools to integrate epigenomic and transcriptomic (ie. RNA and C&R-Seq) data to uncover the causal
link between H3 serotonylation and gene expression during critical postnatal brain development and in response
to ELS. Using a novel cell-type specific viral construct, I will attenuate ELS-induced H3 serotonylation changes,
to elucidate the functional cell-type specific roles of H3 serotonylation in brain development and its connection
to stress-related behaviors in adulthood. During this phase, I will receive technical training on large-scale data
analysis, integration of cell-type specific “omic” data, and molecular cloning techniques that can be used to create
gene editing tools to manipulate epigenetic modifications such as H3 serotonylation in vivo. In the K00 phase, I
will focus on identifying laboratories for my postdoctoral work, prioritizing expertise in circuit-specific approaches
(circuit characterization/manipulation), functional readouts of neuronal physiology (fiber photometry), and use of
computer vision and machine learning to unbiasedly quantify animal behaviors. Together, this tra...

## Key facts

- **NIH application ID:** 11075552
- **Project number:** 1F99NS139541-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ashley Cunningham
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11075552

## Citation

> US National Institutes of Health, RePORTER application 11075552, Cell-type Specific Roles for H3 Serotonylation During Critical Periods of Postnatal Brain Development and Plasticity (1F99NS139541-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11075552. Licensed CC0.

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