XIST Self-regulates its Association with THOC2 and the Nuclear Epigenetic Machinery via miR-186 in Alzheimer's disease

Alzheimer's disease (AD) shows a female bias, with about two-thirds of cases occurring in women; however, the underlying reasons remain unclear. This study uncovers the role of the long non-coding RNA (lncRNA) XIST, a key regulator of X-chromosome inactivation (XCI), in driving female-specific AD pathology. Analyses of single-nucleus RNA sequencing (snRNA-seq) data from human AD cortical tissues and in vitro AD models reveal a notable increase and abnormal cytoplasmic localization of XIST, a phenomenon not previously observed in neurodegeneration. Mechanistically, altered EZH2 levels dampen the trimethylation of histone H3 at lysine 27 (H3K27me3) on the inactive X chromosome, disrupting epigenetic silencing. This dysregulation impacts the RNA export factor subunit THOC2, whose levels are also elevated in AD. Cytoplasmic XIST acts as a competing endogenous RNA (ceRNA) by binding to miR-186-5p, rescuing EZH2 and THOC2 transcripts. This creates a positive feedback loop that sustains both nuclear epigenetic machinery and cytoplasmic post-transcriptional regulation by XIST. The miR-186/EZH2/THOC2/XIST axis offers a molecular framework for understanding the female-biased vulnerability in AD, linking XIST-driven epigenetic changes with nuclear RNA export pathways via cytoplasmic XIST. Disrupted EZH2-XIST interaction reduces H3K27me3 marks on the inactive X chromosome, while increased THOC2 promotes THOC2 (TREX) binding to XIST, maintaining the harmful feedback. Our findings suggest a novel mechanism through which XIST gets recruited to the nuclear export pathways in AD. These results position XIST as a key epigenetic and post-transcriptional regulator in female AD pathophysiology and suggest it could be a target for sex-specific therapeutic interventions.