# Epigenetics of Down Syndrome

> **NIH NIH R01** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2020 · $1,260,080

## Abstract

Achieving a better understanding of the pathogenesis of Down syndrome (DS; trisomy 21) is important for
improving the quality of life of people with DS and for understanding major phenotypes, including intellectual
disability, autoimmunity, cardiac defects, Alzheimer’s disease, and cancer susceptibility and resistance, which
are prominent in DS and are also highly relevant to the general population. Recently we carried out epigenetic
profiling, focusing on DNA methylation, in grey matter and purified neurons and glial cells from autopsy brains,
as well as T-lymphocytes, from individuals with DS vs. matched normal controls. We found highly recurrent
DS-specific differences in methylation patterns (DS-DM), and observed tissue-specificity of the DS-DM, onset
of the altered methylation patterns at the fetal stage, and altered mRNA expression (DS-DE) of only a subset
of the affected genes. We found that CpGs in specific classes of transcription factor binding sites (TFBS) were
preferentially affected, implicating altered TFBS occupancy as a mechanism in shaping the patterns of DS-DM.
Additionally, we carried out whole genome bisulfite sequencing (WGBS) on brains from mouse models of DS,
compared to wild-type littermates, and found alterations in methylation patterns that significantly paralleled
those in the human brains. Motivated by these findings, we now seek to answer three questions – all using
well-controlled mouse models of DS carrying chromosomal triplications. First, to understand the molecular
consequences of DS-DM we will identify DM genes in the mouse models and determine which of them have
differential mRNA expression. We will address this question in purified cell types: T cells and GABAergic
neurons. Second, we will test two hypotheses for the trans-acting mechanisms of DS-DM: (i) the abnormal
methylation is due to over-expression of methylation pathway genes, including Dnmt3l and others, in the
triplicated chromosome regions, and/or (ii) the abnormal patterns of methylation are shaped by overexpression
of specific TF genes in the triplicated regions, leading to altered TFBS occupancy followed by altered CpG
methylation in and around these sites. We will transfer segmental deletions and/or knockout alleles of
individual genes into the DS mouse models to normalize gene dosage, and use WGBS and phenotyping to ask
whether specific components of the DM and specific phenotypes are affected, respectively, in the offspring
carrying the compound mutations. Third, we will apply state-of-the-art genomic assays to ask whether
chromatin architecture within the cell nucleus is altered by the presence of the extra genetic material, and
whether this alteration in turn affects DNA methylation, gene expression and phenotypes. Success of our
project will identify effector and target genes for DS-DM and unravel the mechanisms underlying DS-DM. We
expect that these data will significantly improve our understanding of DS pathogenesis and have broad
implicat...

## Key facts

- **NIH application ID:** 9977004
- **Project number:** 5R01HD090180-05
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Benjamin Tycko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,260,080
- **Award type:** 5
- **Project period:** 2017-09-13 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977004

## Citation

> US National Institutes of Health, RePORTER application 9977004, Epigenetics of Down Syndrome (5R01HD090180-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9977004. Licensed CC0.

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