
複数硬化症患者の一部では、インテグレーター複合体の活性低下が、非コーディングRNA及びRNA ポリメラーゼIIの制御異常を引き起こし、広範な転写体の変化をもたらす。


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HP1α/CBX5 is an epigenetic regulator with a suspected role in multiple sclerosis (MS). Here, using high-depth RNA sequencing on monocytes, we identified a subset of MS patients with reduced CBX5 expression, correlating with progressive stages of the disease and extensive transcriptomic alterations. Examination of rare non-coding RNA species in these patients revealed impaired maturation/degradation of U snRNAs and enhancer-RNAs, indicative of a reduced activity of the Integrator, a complex with suspected links to increased MS risk. At protein-coding genes, compromised Integrator activity manifested in reduced pre-mRNA splicing efficiency and altered expression of genes regulated by RNA polymerase II pause-release. Inactivation of Cbx5 in the mouse mirrored most of these transcriptional defects and resulted in hypersensitivity to Experimental Autoimmune Encephalomyelitis (EAE). Collectively, our observations suggested a major contribution of the Integrator complex in safeguarding against transcriptional anomalies characteristic of MS, with HP1α/CBX5 emerging as an unexpected regulator of this complex’s activity. These findings bring novel insights into the transcriptional aspects of MS and provide potential new criteria in patient stratification.

### Competing Interest Statement

The authors have declared no competing interest.

Defective Integrator activity shapes the transcriptome of patients with multiple sclerosis

複数硬化症患者の転写体に形状を与える欠陥のあるインテグレーター活性