# Gene regulation from the inactive X in activated B cells

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $505,681

## Abstract

Project Summary
The X-chromosome is enriched with immunity-related genes, therefore X-linked genes need to be regulated to
prevent abnormal expression. Females use X-chromosome Inactivation (XCI) to equalize X-linked gene
expression, where one X maintained transcriptionally silent by continuous expression of the long noncoding
RNA Xist and enrichment of heterochromatin modifications. We have recently discovered that female
lymphocytes have a unique and dynamic mechanism to maintain XCI, unlike other somatic cells. Resting
mature B cells lack Xist RNA and heterochromatin marks on the Xi, and these modifications return to the Xi
through a YY1-mediated mechanism upon stimulation. Our in-press work indicates that preventing Xist RNA
localization to the Xi by conditional knock-out of YY1 impairs heterochromatin enrichment on the Xi, and
increases X-linked expression. In preliminary work, we found that B-cell specific deletion of one Xist allele
(mb1CRE XistCKO/+) dramatically reduced Xist localization patterns over the Xi, reduced heterochromatin
enrichment, and increased expression of specific X-linked genes. Moreover, this increase in X-linked gene
expression was accompanied by increased antibodies to double-stranded DNA, a hallmark of autoimmunity.
We hypothesize that Xist RNA localization to Xi is required to keep Xi at the nuclear periphery to maintain
transcriptional repression in activated B cells, and that failure to localize Xist RNA disrupts Xi nuclear
organization and perturbs X-linked gene expression, with consequent predisposition to autoimmunity. We will
test our hypothesis with the following aims: (1) Do temporal and sequence-specific occupancy of YY1, Xist
RNA, and heterochromatin marks on the Xi maintain transcriptional repression in activated splenic B cells? (2)
Do chromosome structural proteins cooperate with YY1 to localize Xist RNA within Xi territory at the nuclear
periphery for transcriptional repression in activated splenic B cells? (3) Are Cxcr3, Itm2a, Syn1 and Cfp
overexpressed in lupus mouse models and does increased dosage predispose to autoimmunity? IMPACT: The
results from these experiments will yield fundamental insight about the lymphocyte-specific mechanisms that
regulate expression from the Xi, and will advance our understanding of the female-bias underlying B cell
mediated autoimmune disorders.

## Key facts

- **NIH application ID:** 10397666
- **Project number:** 5R01AI134834-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Montserrat C Anguera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $505,681
- **Award type:** 5
- **Project period:** 2018-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397666

## Citation

> US National Institutes of Health, RePORTER application 10397666, Gene regulation from the inactive X in activated B cells (5R01AI134834-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10397666. Licensed CC0.

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