# AGING-RELATED REACTIVATION OF X CHROMOSOME GENES

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 1993 · $184,820

## Abstract

Incorrect regulation of gene expression is observed during mammalian
aging and may contribute to the pathology of senescence.  One class of
genetic misregulation is the reactivation of previously repressed genes.
The proposed experiments will examine the aging-related re-expression of
genes from inactive Xchromosomes.  Inactivated X chromosomes of female
mammals are transcriptionally repressed and maintained as
highly-condensed, late-replicating heterochromatic DNA.  The mechanism
for maintenance of X-inactivation is uncharacterized, as are the DNA
sequences which contribute to the inactive state.  In addition,
X-inactivation may share common features with the maintenance of other
forms of heterochromatin and the programmed inactivation of autosomal
genes.

Two genetic loci from the mouse X chromosome, sparsefur and Mottled, have
previously been shown to undergo aging-dependent reactivation.  However,
it has not been demonstrated that reactivation is a general phenomenon of
X-linked genes.  For this proposal, transcriptional reactivation will be
examined from a defined set of X-chromosome genes during normal aging.
In the female mouse, alleles from each X-chromosome homologue can be
assayed independently.  Allele-specific expression assays are based on
naturally-occurring RNA sequence polymorphisms between interbreeding
mouse species.  Interspecific hybrid (F1) females maintain one
X-chromosome from each parental species.  Consequently, these animals are
heterozygous for alleles at virtually every genetic locus.  For each
locus tested, RNA polymorphism assays will be used to detect the relative
contribution from each allele in mRNA samples prepared from aged F1
female mice.  Aging-dependent reactivation will be detected as increased
mRNA expression from the initially repressed allele.

The proposed experiments will focus on the reactivation time-course of
genes within the X-chromosomal region adjacent to the centromere.  The
X-pericentromere is a unique genomic location where inactive-X
heterochromatin and centromeric heterochromatin may contribute
overlapping effects to expression.  In addition, the approximate 3 cM
centromere-proximal region contains several characterized genetic and
molecular loci, including the known reactivated gene ornithine
transcarbamylase (Otc=sparsefur).  The high density of genomic mapping
resources for the region will expedite assembly of a comprehensive
physical map.  Such a map will be essential for assessing relationships
between gene location and aging-dependent reactivation.

## Key facts

- **NIH application ID:** 3123223
- **Project number:** 1R01AG011249-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **SAM.gov UEI:** GNJ7BBP73WE9
- **Principal Investigator:** David T. BURKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $184,820
- **Award type:** 1
- **Project period:** 1993-01-01 → 1997-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3123223

## Citation

> US National Institutes of Health, RePORTER application 3123223, AGING-RELATED REACTIVATION OF X CHROMOSOME GENES (1R01AG011249-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3123223. Licensed CC0.

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