# Delineating a role for histone modifications in Down syndrome using human cellular models

> **NIH NIH R01** · BROAD INSTITUTE, INC. · 2022 · $285,042

## Abstract

SUMMARY
Down syndrome (DS), driven by an extra copy of chromosome 21, is associated with profound changes in
genome-wide gene expression and DNA methylation, but underlying mechanisms remain incompletely
resolved. Leveraging human induced pluripotent stem cell (iPSC) models to capture molecular mechanisms
relevant for human development, we previously identified a significant decrease in the abundance of a specific
histone modification, histone H3 lysine 36 dimethylation (H3K36me2), in DS patient cells compared with
euploid controls; this finding was also highly reproducible across a panel of DS patient and euploid control
lymphoblastoid cell lines, indicating the finding extends to some peripheral cell types. H3K36me2 is localized to
euchromatin where it impacts transcriptional regulation and is essential for maintenance of DNA methylation
via DNMT3A recruitment, particularly at intergenic regions. Notably, haploinsufficiency of the histone
methyltransferase which catalyzes H3K36me2 drives a neurodevelopmental disorder called Sotos syndrome,
characterized by reduced H3K36me2, transcriptional dysregulation and DNA hypomethylation. The profound
developmental consequences of reduced H3K36me2 in Sotos syndrome supports the novel hypothesis that
the reduced H3K36me2 we found in DS could also contribute to developmental abnormalities in this disease
context. Our overall hypothesis is that reduced H3K36me2 in DS drives DNA hypomethylation and
transcriptional dysregulation, and that normalization of H3K36me2 will partially rescue these
phenotypes. In Aim I, we will test the hypothesis that decreased H3K36me2 drives DNA hypomethylation in
DS, by generating genome-wide DNA methylation maps and integrating them with existing H3K36me2 gene
occupancy and transcriptional datasets, all from the same DS patient and isogenic euploid control iPSC-
derived glutamatergic neurons. Importantly, these experiments are designed to connect a well-characterized
phenotype in DS (aberrant DNA methylation) with a novel molecular mechanism (reduced H3K36me2). In Aim
II, we will test the hypothesis that normalizing H3K36me2 levels in DS patient iPSC-derived neurons can
rescue DNA methylation phenotypes. These data would serve as proof-of-principle that inhibition or activation
of specific epigenetic modifiers can reverse well-characterized phenotypes in DS, using physiologically
relevant human cellular models. Collectively, our rigorous molecular analyses will elucidate novel mechanisms
of epigenetic dysregulation in DS, which may ultimately inform on new therapeutic strategies for DS patients;
they will also generate an essential roadmap for future studies to further investigate how reduced H3K36me2
and its normalization impacts iPSC-derived and peripheral blood cell phenotypes.

## Key facts

- **NIH application ID:** 10595812
- **Project number:** 3R01HD101534-01A1S1
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Lindy Elise Barrett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $285,042
- **Award type:** 3
- **Project period:** 2022-08-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10595812

## Citation

> US National Institutes of Health, RePORTER application 10595812, Delineating a role for histone modifications in Down syndrome using human cellular models (3R01HD101534-01A1S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10595812. Licensed CC0.

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