# Evolution of Mammalian Sex Chromosome Dosage Compensation

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $896,013

## Abstract

Abstract
 Mammalian dosage compensation equalizes X-linked gene expression between XX females and XY
males. Defective dosage compensation can cause cell and organismal lethality. Current models posit that
mammalian dosage compensation requires X-inactivation and that X-inactivation requires the X-linked Xist
long noncoding RNA. Despite much work, however, whether Xist and X-inactivation are essential for dosage
compensation remains unclear. The goal of this proposal is to define how mammalian dosage compensation
originated and evolved. The overall objectives of this proposal are to (i) determine the temporal and tissue-
specific requirement of Xist RNA and X-inactivation in dosage compensation; and, to (ii) test the contributions
of ancestral and evolutionarily conserved X chromosome-encoded factors in dosage compensation in the
mouse model system. The central hypothesis of the proposal is that mammalian dosage compensation
originated independently of Xist and X-inactivation and that ancestral X chromosome-encoded factors
equalized X-linked gene expression between the sexes. The rationale for this proposal is that it provides
insights into how cells manage differences in their sex chromosome complements specifically and how cells
equalize gene expression despite differences in chromosome copy number more generally. The proposal's
central hypothesis will be tested through the following approaches: 1) determine the requirements of Xist RNA
and X-inactivation in dosage compensation in the epiblast lineage, which generates all somatic tissues; and, 2)
test the contributions of two ancestral X chromosome-encoded genes in dosage compensation in the absence
Xist and X-inactivation. Dosage compensation will first be analyzed in homozygous Xist-null (XistD/D) female
mouse embryos, embryonic stem cell (ESC)-derived epiblast-like cells (EpiLCs) and neural progenitor cells
(NPCs), and tissues of XistD/D female mice, which we have found to be viable and fertile. Next, X chromosome
dosage compensation will be tested in embryos, EpiLCs, NPCs, and tissues of adult mice that lack Xist and
also one or both alleles of the candidate ancestral dosage compensation factors. The proposed research is
innovative and potentially transformative because it defines novel and Xist- and X inactivation-independent
mechanisms of mammalian dosage compensation using advanced transcriptomic and chromatin profiling
techniques. In the absence of Xist and X-inactivation, the proposal's central hypothesis predicts that the
ancestral candidate genes execute dosage compensation either through random monoallelism or by
simultaneously diminishing expression from both alleles of X-linked genes in XX female cells. The significance
of the proposal is that it will define when, where, and which genes Xist RNA silences during development and
delineate the functions of ancestral X-linked genes in novel Xist- and X inactivation-independent modes of
dosage compensation. Overall, the proposal promise...

## Key facts

- **NIH application ID:** 10918738
- **Project number:** 1R01HD118514-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** SUNDEEP KALANTRY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $896,013
- **Award type:** 1
- **Project period:** 2024-09-11 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918738

## Citation

> US National Institutes of Health, RePORTER application 10918738, Evolution of Mammalian Sex Chromosome Dosage Compensation (1R01HD118514-01). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10918738. Licensed CC0.

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