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Dissertation
A Role for XIST in the Regulation of Inflammatory Response by Female Cells
Doctor of Philosophy (Ph.D.), Drexel University
26 Jan 2017
DOI:
https://doi.org/10.17918/etd-9409
Abstract
Biological sex influences inflammatory response [1]. There is a greater incidence of acute inflammation in men, and chronic inflammation in women. X-inactive specific transcript (XIST) is a long noncoding RNA (lncRNA) crucial for equalizing expression of X-linked genes between females and males. Xist was upregulated in animal and cellular models of acute inflammation. Our in vitro and in vivo experiments and studies from patients with complex regional pain syndrome (CRPS) show that miR-34a could play a role in regulating XIST under inflammation directly and through the regulation of Yin-Yang 1 (YY1). We observed changes in subcellular localization of Xist in J774A.1 female macrophages and an upregulation of Xist RNA in the cytoplasm after inflammatory stimulus. There was a reciprocal regulation between Xist and pro-inflammatory cytokines involving the NF-[kappa]B pathway. Under acute inflammation, Xist associates with NF-[kappa]B in the cytoplasm and inhibits its nuclear migration, thereby reducing acute inflammatory response. Transfection of male THP-1 cells with a 5 kb fragment of the 5' XIST significantly reduced IL-6 expression, NF-[kappa]B activation and migration into the nucleus. Adoptive transfer of splenocytes overexpressing Xist reduced acute paw swelling in male mice induced by complete Freund's adjuvant (CFA). These findings suggest that XIST can have a protective anti-inflammatory effect in females that can contribute to sex-specific differences underlying acute inflammatory response. Thus, XIST can have a role beyond X chromosome inactivation, in the cytoplasm. We propose that the aberrant role of XIST could contribute to the predominance of chronic pain and autoimmune disorders in women and warrants further investigations into the dual role of XIST under acute and chronic inflammation.
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Details
- Title
- A Role for XIST in the Regulation of Inflammatory Response by Female Cells
- Creators
- Botros Shenoda - DU
- Contributors
- Seena Ajit (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 9409; 991014632245504721