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New Mechanisms of X-Chromosome Inactivation Contribute to the Female Bias of Lupus
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | New Mechanisms of X-Chromosome Inactivation Contribute to the Female Bias of Lupus. |
| 개인저자 | Syrett, Camille M. |
| 단체저자명 | University of Pennsylvania. Cell and Molecular Biology. |
| 발행사항 | [S.l.]: University of Pennsylvania., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 212 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-04B. Dissertation Abstract International |
| ISBN | 9781088366356 |
| 학위논문주기 | Thesis (Ph.D.)--University of Pennsylvania, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Advisor: Anguera, Montserrat C. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | The X chromosome is highly enriched for genes with critical immune regulatory functions. Intriguingly, autoimmune disorders like systemic lupus erythematosus are more prevalent in individuals with two X chromosomes such as XX women and XXY men with Klinefelter syndrome. In females, the long noncoding RNA Xist initiates and maintains X-chromosome inactivation (XCI), where a single X chromosome is transcriptionally silenced to equalize X-linked gene dosage between the sexes. The paradigm of XCI is that all female somatic cells maintain silencing of the inactive X chromosome (Xi) through continuous Xist RNA localization and heterochromatin enrichment at the Xi. Importantly, increased X-linked gene expression is observed in lupus, yet the precise mechanism responsible for this transcriptional increase is unclear. Here, we perform an in-depth examination of the unique and dynamic maintenance of XCI in female murine immune cells. Remarkably, some lymphoid and myeloid lineage cells, including naive lymphocytes, lack the canonical enrichment of Xist RNA and heterochromatin at the Xi. These epigenetic features return back to the Xi in the B cell lineage during in vitro activation in a two-step mechanism dependent on the transcription factor YY1. Importantly, deleting YY1 in activated B cells disrupts the localization of Xist RNA to the Xi and increases X-linked gene expression, suggesting that Xist RNA is required at the Xi in activated lymphocytes to mediate dosage compensation. Thus, we hypothesized that Xist RNA is mislocalized in activated lymphocytes from females with lupus, thereby altering X-linked gene dosage and contributing to the overexpression of X-linked immune genes observed during autoimmunity. Indeed, using a murine model of female-biased lupus-like disease, we find evidence for the mislocalization of Xist RNA and altered expression of X-linked genes in activated lupus lymphocytes. Together, we uncover a new mechanism for the dynamic maintenance of XCI in female immune cells, and we discuss the important contribution of Xist RNA localization to female-biased autoimmunity. |
| 일반주제명 | Genetics. Biology. Immunology. |
| 언어 | 영어 |
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