# Mechanisms of escaping X chromosome inactivation and translation to X-linked disease

> **NIH NIH R35** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $392,431

## Abstract

Abstract
 In mammals, male X hemizygosity neccesitates dosage compensation of X-linked
genes by means of X chromosome inactivation (XCI) in XX females. Because either X
chromosome can be silenced, heterozygous females are typically mosaic for expression
of parental alleles and therefore less susceptible to X-linked disorders than hemizygous
males. When XCI is skewed however, disease penetrance rises with the fraction of cells
that have silenced the functional allele. As a result, both males and females are exposed
to the cumulative burden of monogenic disease harbored on the X chromosome.
 Yet, the inactive X chromsome (Xi) is not entirely silent: some genes, in particular
those with paralogous copies on the Y chromosome (X-Y gene pairs), are exempt from
dosage compensation and escape XCI. Turner syndrome (TS, karyotype 45,X) reflects a
sensitivity to the dosage of such “escapee” genes, and adds to the significant X-linked
health burden through cardiovascular and renal malformations, as well as high rates of
spontaneous termination of 45,X conceptuses.
 Much of the XCI field has focused on implicating and dissecting requisite gene
silencing pathways, using the mouse X as the primary model. In contrast, the
mechanism(s) that enable escapees to sustain expression from an otherwise repressed
chromosome territory have received little attention, especially in humans. As a result, the
identity, lineage-specificity, and regulatory mechanisms of escapees remain unresolved.
Building on our allele-specific genomics and XCI expertise, we propose to address these
questions in otherwise isogenic 45,X/46,XX human pluripotent stem cells. This platform
will enable us to 1.) quantify allele-specific expression across the human X and along
distinct cell lineages, 2.) dissect the local and long-range regulatory logic of escapees,
and 3.) assess dosage-sensitive contributions of individual escapees.
 These advances will aid the interpretation of human X-linked variants, complement an
expanding glossary of gene regulatory elements, and reveal how escapees manage to
resist silencing. Such mechanstic insights may yield novel means of manipulating
regulatory elements, and subsequently translate into generalized, epigenetic approaches
to X-linked disease in heterozygous females, as well as gene dosage correction in TS
and other dosage-sensitive disorders in the human genome.

## Key facts

- **NIH application ID:** 9985969
- **Project number:** 5R35GM124926-04
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Stefan F. Pinter
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,431
- **Award type:** 5
- **Project period:** 2017-09-11 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985969

## Citation

> US National Institutes of Health, RePORTER application 9985969, Mechanisms of escaping X chromosome inactivation and translation to X-linked disease (5R35GM124926-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9985969. Licensed CC0.

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