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Mechanism and Function of XIST in X Chromosome Inactivation Maintenance

Award Number: R35GM162709
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Mechanism and Function of XIST in X Chromosome Inactivation Maintenance - PROJECT SUMMARY X chromosome inactivation (XCI) is essential in equalizing X-linked gene expression between females (XX) and males (XY). This process is initiated by XIST, a female-specific long non-coding RNA (lncRNA) that recruits diverse co-factors to epigenetically silence the prospective inactive X chromosome (Xi) during embryogenesis. Once established, the Xi “remembers” to maintain silencing in all somatic cells through adulthood, serving as a unique epigenetic memory model. In contrast to the significant progress made to understand XCI initiation, the mechanism and function underlying XCI maintenance remain largely unknown. We recently uncovered an unexpected requirement of XIST in maintaining X-inactivation, a process that is long thought to be independent of XIST. Specifically, we found that XIST prevents the escape of key immune-associated genes from X- inactivation in somatic B cells. Building on our preliminary work, we hypothesize that XIST orchestrates XCI maintenance through evolutionarily conserved domains in a cell-type-specific and signaling-responsive manner, particularly in somatic immune cells. Over the next five years, we will test this hypothesis by answering three fundamental questions: (1) How do XIST's functional domains coordinate to maintain X-inactivation? (2) How do cellular signaling pathways influence XCI maintenance fidelity? (3) When and where is XIST required for XCI maintenance throughout lifespan? We will address these questions using CRISPR perturbation, allele-specific chromatin profiling, RNA mediated proteomics, single-cell genomics and mouse models with clonal XCI tracking ability. This comprehensive strategy will allow us to understand how XIST safeguards Xi silencing against gene escape and female-biased diseases. Completion of this work will reveal fundamental principles of non-coding RNA mediated epigenetic regulation, provide valuable toolkits for broader epigenetic and lncRNA community, and expand the role of X-inactivation maintenance in sex dimorphism of immune compartment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $456,500 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	2/9/2026	NEW	$456,500
														Subtotal = $456,500

Grand Total All Awards = $456,500

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Mechanism and Function of XIST in X Chromosome Inactivation Maintenance

Award Number: R35GM162709

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/15/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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