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Updated: Jun 18, 2025

A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
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A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations

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

Majid Pahlevan Kakhki1, Antonino Giordano1,2,3,4, Chiara Starvaggi Cucuzza1,5

  • 1Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.

Nature Communications
|July 30, 2024
PubMed

Insights

Researchers uncovered a genetic-epigenetic interplay in primary progressive multiple sclerosis (PPMS). This involves the 1q21.1 locus, impacting gene expression and potentially driving neurodegeneration in PPMS.

Area of Science:

  • Neuroscience
  • Genetics
  • Epigenetics

Background:

  • Multiple Sclerosis (MS) presents as a complex inflammatory and neurodegenerative condition with variable progression.
  • Effective treatment for progressive MS forms remains difficult due to incomplete understanding of disease mechanisms.

Purpose of the Study:

  • To investigate molecular alterations in primary progressive MS (PPMS) by analyzing genetic, epigenetic, and transcriptomic data across blood and brain tissues.
  • To identify specific molecular pathways and genetic variations contributing to PPMS pathogenesis.

Main Methods:

  • Utilized a multi-omics approach, integrating genetic, epigenetic (DNA methylation), and transcriptomic data from independent patient cohorts.
  • Employed reporter assays and CRISPR/dCas9 gene editing to establish causal relationships between methylation and gene expression.
  • Conducted gene knockdown in human neurons and knockout in zebrafish models to assess functional consequences.

Main Results:

  • Identified hypermethylation at the 1q21.1 locus in PPMS, influenced by specific genetic variations.
  • Demonstrated that this methylation pattern affects the expression of nearby genes, CHD1L and PRKAB2, in the brain.
  • Confirmed a causal link between methylation and gene expression, implicating these genes in PPMS-related brain processes.
  • Showcased that CHD1L deficiency leads to neuronal developmental and functional deficits.

Conclusions:

  • A distinct genetic-epigenetic-transcriptional interaction at the 1q21.1 locus is suggested to play a role in the pathogenesis of PPMS.
  • These findings provide novel insights into the molecular underpinnings of progressive MS, potentially opening avenues for targeted therapies.

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