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

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, a master regulator of X-chromosome inactivation (XCI), as a driver 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 reported in neurodegeneration. Reduced EZH2 levels in AD impair histone H3 lysine-27 trimethylation (H3K27me3) on the inactive X chromosome, disturbing epigenetic silencing. The epigenetic dysregulation elevates the X-linked RNA export factor THOC2, which par