A genetic-epigenetic interplay at 1q21.1 locus underlies CHD1L-mediated vulnerability to primary progressive multiple sclerosis.
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Pahlevan Kakhki M, Giordano A, Starvaggi Cucuzza C, Venkata S Badam T, Samudyata S, Lemée MV, Stridh P, Gkogka A, Shchetynsky K, Harroud A, Gyllenberg A, Liu Y, Boddul S, James T, Sorosina M, Filippi M, Esposito F, Wermeling F, Gustafsson M, Casaccia P, Hillert J, Olsson T, Kockum I, Sellgren CM, Golzio C, Kular L, Jagodic M
Nat Commun 15 (1) 6419 [2024-07-30; online 2024-07-30]
Multiple Sclerosis (MS) is a heterogeneous inflammatory and neurodegenerative disease with an unpredictable course towards progressive disability. Treating progressive MS is challenging due to limited insights into the underlying mechanisms. We examined the molecular changes associated with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. In PPMS, we found hypermethylation of the 1q21.1 locus, controlled by PPMS-specific genetic variations and influencing the expression of proximal genes (CHD1L, PRKAB2) in the brain. Evidence from reporter assay and CRISPR/dCas9 experiments supports a causal link between methylation and expression and correlation network analysis further implicates these genes in PPMS brain processes. Knock-down of CHD1L in human iPSC-derived neurons and knock-out of chd1l in zebrafish led to developmental and functional deficits of neurons. Thus, several lines of evidence suggest a distinct genetic-epigenetic-transcriptional interplay in the 1q21.1 locus potentially contributing to PPMS pathogenesis.
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 39079955
DOI 10.1038/s41467-024-50794-z
Crossref 10.1038/s41467-024-50794-z
pmc: PMC11289459
pii: 10.1038/s41467-024-50794-z