# Sex-specific trajectories in epigenomic regulation of brain patterning

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $943,862

## Abstract

The core concept of our proposed studies is that sex-biased gene expression early in human
development pattern the brain differently in males and females, and that this patterning underlies
differential susceptibility of males and females to neurodevelopmental disorders. We envision that
these sex differences are regulated by epigenetic programs controlling the expression of
developmentally regulated genes in a sex-biased manner. We further postulate that these sex-
dependent epigenetic mechanisms interact with genetic risk factors that influence risk,
progression, and severity of autism sprectrum disorders (ASD) and schizophrenia (SCZ), and we
will test these hypotheses in two specific aims. Aim 1 is to delineate the sex-dependent regulation
of early brain development in typical individuals. Epigenetic and gene expression programs in
brain organoids and postmortem fetal brains will be evaluated on multiple levels, including
transcriptome, proteome, and activity of noncoding regulatory elements. The objective of this aim
is to define a network of genes and their regulatory elements—primarily enhancers—that are
differentially active between males and females during early brain development. Aim 2 will
determine whether the sex-biased regulatory network carries an increased burden of potentially
pathogenic or risk associated genetic variants in developmental disorders such as SCZ and ASD.
We will query available genome sequencing and GWAS datasets of probands and typical controls
to determine whether the sex-biased regulatory network are enriched for rare and common
inherited disease variants. Enrichment of these variants in the sex-biased regulatory network will
reveal potential mechanisms by which sex-biased gene expression affects SCZ and ASD genetic
risk and trajectory. The impact of this work is seeking the first detailed understanding of early
sexually dimorphic brain development. The new knowledge will constitute a fundamental advance
in our understanding of normal development, and will pioneer the discovery of how disease
susceptibility depends on sex-biased gene regulation in the developing brain.

## Key facts

- **NIH application ID:** 10807974
- **Project number:** 5R01MH129301-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** FLORA M VACCARINO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $943,862
- **Award type:** 5
- **Project period:** 2022-04-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807974

## Citation

> US National Institutes of Health, RePORTER application 10807974, Sex-specific trajectories in epigenomic regulation of brain patterning (5R01MH129301-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10807974. Licensed CC0.

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