# Dosage Sensitivity of Gene Expression in Pluripotent Stem Cells in the context of Down Syndrome

> **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $28,613

## Abstract

PROJECT SUMMARY
Gene dosage and regulation of gene expression levels are important to proper maintenance of cellular
function, yet how these levels are coordinated and balanced is little understood. Events such as segmental
duplications and aneuploidy can disrupt the dosage balance of gene expression; specific genes sensitive to
this change can lead to disease. Understanding of dosage sensitivity may provide insight into these types of
complex genetic disorders but this has not been comprehensively studied in humans. To investigate dosage
sensitivity, Down syndrome (DS) may prove to be both a useful and important disease model, as it is the most
common form of aneuploidy in humans, with 1 in 700 live births. DS is caused by trisomy of chromosome 21
(chr21) and it is unknown how many genes are major contributors of DS pathology. There are over 400 genes
on chr21 but it is likely that only a subset of dosage sensitive genes is responsible for the pathology.
Additionally, it can be difficult to discern which chr21 genes are likely to be dosage sensitive from
transcriptomic studies. Thus, additional study on genome-wide effects of the extra chr21 in DS is needed as
well as a better method to identify and prioritize chr21 dosage sensitive genes. In this proposal, I seek to study
dosage sensitivity in the context of Down syndrome, first, by investigating transcriptome-wide effects of trisomy
21 through the use of induced pluripotent stem cells (iPSCs), second, examining the contributions of candidate
chr21 dosage sensitive genes involved in DS pathology, and finally, through the use of bioinformatics analysis,
extend methods of identifying and prioritizing candidate chr21 dosage sensitive genes.
AIM 1: Recently, our lab has developed a chromosomal silencing system in iPSCs through the use of an XIST
transgene, comprehensively silencing the extra chr21 in DS iPSCs. I will use this DS iPSC silencing system to
study the dosage effects on the transcriptome by comparing the extra chr21 silenced and non-silenced DS
iPSCs. This will allow us to observe the earliest and direct biological effect of trisomy silencing which will be
important to understanding DS pathogenesis.
AIM 2: With the advent of CRISPR technologies, we are able to precisely modulate gene dosage in DS iPSCs
cells. Using candidate chr21 genes in DS identified by preliminary microarray data, I will generate single allele
knockout DS iPSC lines to determine the single gene contributions to DS cellular phenotypes. With the specific
genetic context of DS, I will be able to examine the underlying mechanisms that are relevant to DS pathology.
AIM 3: It has been suggested that dosage sensitivity is correlated with low expression variability, but this has
not been extensively studied in humans. While a few predictive models for dosage sensitivity exist, they are not
comprehensive and did not include expression variability as a parameter. Therefore, I will take a genome-wide
approach to examine the gen...

## Key facts

- **NIH application ID:** 9994381
- **Project number:** 5F31HD095588-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Jennifer Eun-Mi Moon
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $28,613
- **Award type:** 5
- **Project period:** 2018-08-21 → 2021-06-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994381

## Citation

> US National Institutes of Health, RePORTER application 9994381, Dosage Sensitivity of Gene Expression in Pluripotent Stem Cells in the context of Down Syndrome (5F31HD095588-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9994381. Licensed CC0.

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