Defective Integrator activity shapes the transcriptome of patients with multiple sclerosis: patient data

While the role of the immune system in multiple sclerosis (MS) is widely acknowledged, our comprehension of the transcriptional foundations of this prevalent neurological disorder remains largely incomplete. Here, we conducted high-depth RNA sequencing on monocytes from a cohort of patients with MS to explore rare RNA species associated with the disease. In a subset of the patients, a markedly altered transcriptome was observed, coinciding with a decreased expression of the epigenetic silencer HP1α/CBX5. These patients also exhibited diminished expression of multiple genes encoding subunits of the Integrator complex. Alongside, there were clear indications of decreased Integrator activity, including impaired U snRNA and enhancer-RNA maturation/degradation and dysregulated RNA polymerase II (RNAPII) pause-release. Inactivation of Cbx5 in the mouse recapitulated the defects in Integrator activity and resulted in hypersensitivity to Experimental Autoimmune Encephalomyelitis (EAE). While these data implied an unexpected function for HP1α in regulating RNAPII pause-release, they also showed that the dysregulation of numerous genes in MS patients could be attributed to either the biased distribution of transcription toward the 5' end of genes or the heightened elongation and stability of enhancer RNAs. An impaired Integrator activity, which has been hinted at by mutations within Integrator subunits previously linked to an increased risk of MS, provides a well-defined mechanistic understanding of the transcriptional anomalies associated with the disease, while introducing new criteria to categorize MS patients. With the objective of obtaining high quality RNA-seq allowing detection of rare RNA species, we collected monocytes from a cohort of 18 MS patients and 7 control patients. To explore eventual changes in the RNA populations induced by the disease progression, we selected a very heterogeneous set including patients with familial MS (#68, #125, and #130 – one family, 3 generations), under immune modulating treatment (#125, #127, #135, #136, and #139), or with comorbidities (psoriasis, IDDM, Graves, Crohn and ulcerative colitis). The control group, designated as symptomatic controls (SCs), comprised individuals who had sought medical assistance for symptoms suggestive of MS, but who, upon examination, exhibited no objective clinical or paraclinical findings conclusive for a specific neurological disease at the time of sample collection (Figure 1A). The RNA-seq analysis was conducted using a stranded paired-end protocol, yielding an output of approximately 110 million reads per sample.