Defective Integrator activity shapes the transcriptome of patients with multiple sclerosis.

Area of Science:

• Molecular Biology
• Epigenetics
• Neuroimmunology

Background:

• Multiple sclerosis (MS) is a neuroinflammatory disease with complex etiology.
• HP1α/CBX5 is an epigenetic regulator implicated in various cellular processes.
• A potential role for HP1α/CBX5 in MS pathogenesis is suspected.

Purpose of the Study:

• To investigate the role of HP1α/CBX5 in multiple sclerosis.
• To identify molecular mechanisms linking CBX5 to MS progression and transcriptional dysregulation.

Main Methods:

• High-depth RNA sequencing of monocytes from MS patients.
• Analysis of non-coding RNA species (U snRNAs, enhancer RNAs).
• Assessment of pre-mRNA splicing efficiency and gene expression.
• Inactivation of Cbx5 in a mouse model of experimental autoimmune encephalomyelitis (EAE).

Main Results:

• A subset of MS patients exhibits reduced CBX5 expression, associated with progressive disease stages.
• Impaired maturation/degradation of U snRNAs and enhancer RNAs suggests reduced Integrator complex activity.
• Compromised Integrator activity leads to reduced pre-mRNA splicing efficiency and altered gene expression.
• Cbx5 inactivation in mice recapitulates transcriptional defects and exacerbates EAE susceptibility.

Conclusions:

• The Integrator complex plays a crucial role in preventing transcriptional anomalies in MS.
• HP1α/CBX5 is an unexpected regulator of the Integrator complex's activity.
• These findings provide novel insights into MS transcriptional pathology and potential patient stratification biomarkers.