# Epigenetic Determinants in Oligodendrocyte Maturation in Down Syndrome

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $453,750

## Abstract

Abstract
 Down Syndrome (DS) or trisomy 21 is caused by triplication of human chromosome 21 (HSA21), and it
is the most common cause of intellectual disability. Triplication of HSA21 includes genes that are involved in
cognition and brain function, as well as myelin production, and exerts global changes in the transcriptomic and
epigenetic landscape in DS. Previous work on humans with DS and DS-mouse models have shown altered
expression of myelin-related genes, as well as delayed OL maturation and disruption in myelin production,
structure, and density. These changes, attributed partially to triplication of oligodendrocyte lineage transcription
factors 1/2 (OLIG1/2), result in impaired myelination and abnormal neuronal conductivity, contributing to the
intellectual deficits associated with DS. In addition to changes in the gene content caused by HSA21 triplication,
there are well-recognized DS-related alterations of normal epigenetic landscape across the genome. These DS-
related epigenetic changes can in turn influence myelination, because commitment and development of
oligodendrocyte (OL) lineage is tightly regulated through the stage-dependent acquisition of repressive
chromatin changes.
 In this project, we will provide the first examination of how changes in the epigenetic machinery alter OL
biology in DS using human patient-derived induced pluripotent stem (iPS) cells. We will use a newly described
3D cellular model of OL spheroids (OLS) that contain oligodendrocyte, astrocyte, and neuronal populations, to
provide a comprehensive, dynamic environment for studying myelination processes. Using this system, we will
fully characterize changes in OL lineage commitment and development in human DS-derived isogenic lines and
examine how these alterations are driven by changes in the epigenetic code regulating OL specification.
 Using fate- and differentiation-specific markers, we will fully characterize the generation and temporal
development of OL lineage through the different maturational checkpoints, as well as the diversity of other
constituent cell populations (including neurons and astrocytes) in trisomic and euploid OLS. Next, we will
determine how the DS-associated epigenetic landscape shapes OL developmental and functional trajectory.
We will reveal transcriptional dynamics and accessibility of chromatin in a variety of cellular populations
developing within euploid and trisomic OLS using the Chromium Single Cell Multiome ATAC+Gene expression
platform (10xGenomics), which combines RNA-seq and ATAC-seq profiling on the same population of cells.
 This will be the first study to directly link transcriptional changes in myelin-producing cells to the altered
epigenomic circuitry in DS. Understanding the epigenetic mechanisms underlying the developmental
vulnerability of these cells will point to novel therapeutic approaches that combine potential epidrugs and
myelination-targeting approaches.

## Key facts

- **NIH application ID:** 10527889
- **Project number:** 1R21NS125469-01A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Maria Medalla
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $453,750
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527889

## Citation

> US National Institutes of Health, RePORTER application 10527889, Epigenetic Determinants in Oligodendrocyte Maturation in Down Syndrome (1R21NS125469-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10527889. Licensed CC0.

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