# X chromosome regulation and role in aneuploidy

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2021 · $706,782

## Abstract

Project Summary/Abstract
Mammalian X chromosome inactivation is a complex epigenetic mechanism that ensures a near-balanced
level of gene expression between males (XY) and females (XX). This chromosome-wide regulation makes the
X an ideal model for studying heterochromatin regulation and structure. X inactivation affects a sizable portion
of the mammalian genome and is crucial for normal development and normal lifespan. Indeed, X aberrations
have been linked to birth defects and to age-related diseases. My research group has made several
contributions to understanding the structure and regulation of the X by developing useful mouse models and
studying human conditions with sex chromosome anomalies, while embracing novel technologies to advance
the field.
Here, I consider challenges related to the physical structure and location of the inactive X within the nucleus,
with a focus on long non-coding RNAs (lncRNAs). By scaffolding proteins into flexible complexes lncRNAs
have emerged as adaptable elements that organize chromatin and regulate gene expression, but many
questions remain unanswered about their mechanisms of action. I will examine the cis- and trans- roles of
conserved X-linked lncRNA loci and their transcripts in regulating the structure and location of the X
chromosome within the nucleus. We found that Dxz4 shapes the unique bipartite structure of the inactive X in
cis and Firre apparently controls the inactive X location and epigenetic features in trans. Here, I propose to
introduce new approaches to manipulate these and other lncRNA loci and to relocate specific X chromosome
regions within the nucleus. This will address the fundamental role of physical location in relation to
heterochromatin formation and maintenance.
Escape from X inactivation in females and the presence of a Y in males lead to sexual dimorphisms in cell
physiology. Cell-type diversity within tissues is extensive but poorly understood; yet, novel exciting new
technologies can measure gene expression and chromatin features in tens of thousands of single cells in vivo.
To address the role of sex-linked genes at the cellular and organismal level I will establish an in vivo atlas of
allelic features in single cells of male and female mouse tissues. Single-cell technology will also be applied to
mouse and human tissues from fetuses and adults with sex chromosome aneuploidy to determine the impact
on cell types. An interesting possibility is that an adaptive developmental epigenetic response to aneuploidy
explains phenotypic variability. To explore this, I will compare epigenetic features in tissues to those obtained
in isogenic cell lines with induced X chromosome loss. My goal is to understand the role of the sex
chromosomes in sex differences and sex chromosome disorders in vivo.

## Key facts

- **NIH application ID:** 10147105
- **Project number:** 5R35GM131745-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Christine M. Disteche
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $706,782
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147105

## Citation

> US National Institutes of Health, RePORTER application 10147105, X chromosome regulation and role in aneuploidy (5R35GM131745-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10147105. Licensed CC0.

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