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

Author

Listed:
  • Majid Pahlevan Kakhki

    (Karolinska University Hospital)

  • Antonino Giordano

    (Karolinska University Hospital
    IRCCS San Raffaele Hospital
    IRCCS San Raffaele Scientific Institute
    Università Vita-Salute San Raffaele)

  • Chiara Starvaggi Cucuzza

    (Karolinska University Hospital
    Academic Specialist Center)

  • Tejaswi Venkata S. Badam

    (Karolinska University Hospital
    Linköping university)

  • Samudyata Samudyata

    (Karolinska Institutet)

  • Marianne Victoria Lemée

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire
    Centre National de la Recherche Scientifique, UMR7104
    Institut National de la Santé et de la Recherche Médicale, U1258
    Université de Strasbourg)

  • Pernilla Stridh

    (Karolinska University Hospital)

  • Asimenia Gkogka

    (Karolinska Institutet)

  • Klementy Shchetynsky

    (Karolinska University Hospital)

  • Adil Harroud

    (The Neuro (Montreal Neurological Institute-Hospital)
    McGill University
    McGill University)

  • Alexandra Gyllenberg

    (Karolinska University Hospital)

  • Yun Liu

    (Fudan University)

  • Sanjaykumar Boddul

    (Karolinska University Hospital)

  • Tojo James

    (Karolinska University Hospital)

  • Melissa Sorosina

    (IRCCS San Raffaele Scientific Institute)

  • Massimo Filippi

    (IRCCS San Raffaele Hospital
    Università Vita-Salute San Raffaele
    IRCCS San Raffaele Hospital
    San Raffaele Scientific Institute)

  • Federica Esposito

    (IRCCS San Raffaele Hospital
    IRCCS San Raffaele Scientific Institute)

  • Fredrik Wermeling

    (Karolinska University Hospital)

  • Mika Gustafsson

    (Linköping university)

  • Patrizia Casaccia

    (Icahn School of Medicine at Mount Sinai)

  • Jan Hillert

    (Karolinska University Hospital)

  • Tomas Olsson

    (Karolinska University Hospital)

  • Ingrid Kockum

    (Karolinska University Hospital)

  • Carl M. Sellgren

    (Karolinska Institutet
    Karolinska Institutet
    Stockholm County Council)

  • Christelle Golzio

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire
    Centre National de la Recherche Scientifique, UMR7104
    Institut National de la Santé et de la Recherche Médicale, U1258
    Université de Strasbourg)

  • Lara Kular

    (Karolinska University Hospital)

  • Maja Jagodic

    (Karolinska University Hospital)

Abstract

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.

Suggested Citation

  • Majid Pahlevan Kakhki & Antonino Giordano & Chiara Starvaggi Cucuzza & Tejaswi Venkata S. Badam & Samudyata Samudyata & Marianne Victoria Lemée & Pernilla Stridh & Asimenia Gkogka & Klementy Shchetyns, 2024. "A genetic-epigenetic interplay at 1q21.1 locus underlies CHD1L-mediated vulnerability to primary progressive multiple sclerosis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50794-z
    DOI: 10.1038/s41467-024-50794-z
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