# Translational Epigenetics with XIST: Silencing Trisomy in Human Organoid and Mouse Models of Down Syndrome

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $569,909

## Abstract

ABSTRACT
The broader vision of this research is to develop the largely unexplored potential for “translational epigenetics”
of XIST RNA and advance understanding and a potential therapeutic strategy for Down Syndrome. Human
XIST/mouse Xist encodes a unique long non-coding RNA with the well-established power to induce stable
epigenetic silencing, in cis. While the basic biology of XIST RNA and X-chromosome dosage compensation is
heavily studied, our lab is working to pioneer the translational potential of XIST dosage compensation for
common chromosomal imbalances, particularly Down Syndrome. Chromosomal abnormalities remain a major,
unaddressed part of the human genetic burden, occurring in 1/140 births. It would be “game-changing” if the
over-expression of hundreds of genes in cells carrying trisomy 21 could be addressed by manipulation of just
one gene, XIST. The Lawrence lab recently demonstrated in vitro that a large XIST cDNA could be accurately
inserted into one chromosome 21 and induce surprisingly comprehensive, stable “trisomy silencing” of the
autosome, shown in undifferentiated iPS cells derived from DS patient cells. We now seek funding to build on
a strong foundation of recent progress in pursuit of the next ambitious goal; to test and develop the longer-term
potential development for trisomy silencing in vivo. To this end, we will investigate XIST-mediated
chromosomal silencing and its ability to reverse or mitigate cell or organism pathology, in human cerebral
organoid and neural cells and in a well-studied trisomic mouse model of DS. In addition to relevance for DS,
our studies have direct relevance for Alzheimer Disease, which occurs almost inevitably and 20-30 years in
individuals with Down Syndrome. By focusing some of our goals on the APP locus, we will test strategies that
target gene therapy for APP as a first step to insertion of XIST transgenes for chromosome therapy. We have
assembled a multi-disciplinary team of co-investigators and collaborators, led by two PIs with complementary
expertise, and together we will test strategies and probe the full potential that XIST RNA provides a versatile
tool for “translational epigenetics” for Down Syndrome and potentially other conditions.

## Key facts

- **NIH application ID:** 9982390
- **Project number:** 5R01HD094788-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** JEANNE Bentley LAWRENCE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $569,909
- **Award type:** 5
- **Project period:** 2018-09-19 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982390

## Citation

> US National Institutes of Health, RePORTER application 9982390, Translational Epigenetics with XIST: Silencing Trisomy in Human Organoid and Mouse Models of Down Syndrome (5R01HD094788-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982390. Licensed CC0.

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