XIST Self-regulates its association with THOC2 and the nuclear epigenetic machinery via miR-186 in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) exhibits a strong female bias, yet the underlying molecular basis remains poorly understood. This study identifies the long non-coding RNA (lncRNA) XIST, the key mediator of X-chromosome inactivation (XCI), as a regulator of female-specific AD pathology. Single-nucleus RNA-seq (snRNA-seq) analyses from human AD cortex and in vitro AD models reveal elevated and abnormally cytoplasmic XIST, a feature not previously studied in neurodegeneration. Reduced EZH2 and histone H3 lysine-27 trimethylation (H3K27me3) levels in AD coupled with reduced colocalization of these proteins with the inactivated X chromosome, signal epigenetic alteration. Among the X-linked genes, RNA export factor THOC2 emerges as a gene of interest, which participates in a feedback loop with XIST. Cytoplasmic XIST on the other hand, functions as a competing endogenous RNA (ceRNA) by sequestering miR-186-5p, thereby maintaining EZH2 and THOC2 transcripts. The present study identifies a XIST/miR-186/EZH2/THOC2 regulatory axis that couples the epigenetic machinery with nuclear RNA export pathways via cytoplasmic XIST in female. XIST thus emerges as an important candidate regulating sex-biased AD pathophysiology.