A genetic-epigenetic interplay at 1q21.1 locus underlies CHD1L-mediated vulnerability to primary progressive multiple sclerosis.

Humans Zebrafish / genetics Epigenesis, Genetic Animals DNA Methylation / genetics Chromosomes, Human, Pair 1 / genetics DNA-Binding Proteins / genetics Brain / metabolism DNA Helicases / genetics Neurons / metabolism Multiple Sclerosis, Chronic Progressive / genetics Induced Pluripotent Stem Cells / metabolism Male Female Middle Aged Genetic Predisposition to Disease Adult

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
30 Jul 2024

Historique:

received: 28 04 2023

accepted: 21 07 2024

medline: 31 7 2024

pubmed: 31 7 2024

entrez: 30 7 2024

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-50794-z PMID: 39079955

pubmed: 39079955

doi: 10.1038/s41467-024-50794-z

pii: 10.1038/s41467-024-50794-z

doi:

Substances chimiques

DNA-Binding Proteins 0

DNA Helicases EC 3.6.4.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

6419

Subventions

Organisme : EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))

ID : 818170

Organisme : Agence Nationale de la Recherche (French National Research Agency)

ID : JCJC ANR-17-CE12-0006

Informations de copyright

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