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bioRxiv · 10.1101/2025.10.05.680468

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

Sen, S.·Mukhopadhyay, D.
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Abstract

Alzheimers 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 participates in a feedback loop with XIST. Cytoplasmic XIST functions as a competing endogenous RNA (ceRNA) by sequestering miR-186-5p, thereby rescuing EZH2 and THOC2 transcripts. The resulting XIST/miR-186/EZH2/THOC2 axis couples XIST-driven epigenetic changes with nuclear RNA export pathways via cytoplasmic XIST. Disrupted EZH2-XIST interaction reduces H3K27me3 marks on the inactive X, while increased THOC2 promotes THOC2(TREX)-XIST interaction, maintaining the harmful feedback. Our findings reveal a novel mechanism through which XIST gets recruited to the nuclear RNA export pathways in AD. XIST thus emerges as a critical node in sex-specific AD pathophysiology and a promising target for therapeutic intervention. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/680468v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1d640d9org.highwire.dtl.DTLVardef@13b8c6eorg.highwire.dtl.DTLVardef@809298org.highwire.dtl.DTLVardef@1186899_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Sen, S., Mukhopadhyay, D.. 2025-10-06. XIST Self-regulates its Association with THOC2 and the Nuclear Epigenetic Machinery via miR-186 in Alzheimer's disease. https://doi.org/10.1101/2025.10.05.680468

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