Defective Integrator activity shapes the transcriptome of patients with multiple sclerosis

Yevheniia Porozhan, Mikkel Carstensen, Sandrine Thouroude, Mickael Costallat, Christophe Rachez, Eric Batsché, Thor Petersen, Tove Christensen, Christian Muchardt*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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 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. 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 for patient stratification.

Original languageEnglish
Article numbere202402586
JournalLife Science Alliance
Volume7
Issue number10
Number of pages17
ISSN2575-1077
DOIs
Publication statusPublished - Oct 2024

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© 2024 Porozhan et al.

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