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Centromere defects, chromosome instability, and cGAS-STING activation in systemic sclerosis

Souren Paul1, Mark H Kaplan2, Dinesh Khanna2,3

  • 1The Hormel Institute, University of Minnesota, Austin, MN, USA.

Nature Communications
|November 18, 2022
PubMed

Insights

Systemic Sclerosis (SSc) fibroblasts exhibit centromere DNA alterations and chromosome instability. These defects link to autoimmunity and fibrosis, suggesting new therapeutic targets for SSc.

Area of Science:

  • Cell Biology
  • Immunology
  • Genetics

Background:

  • Centromere proteins are often discovered in Systemic Sclerosis (SSc) patients, yet centromere defects in SSc remain largely unexplored.
  • Previous research has identified centromere proteins in SSc patients, highlighting a potential connection that warrants further investigation.

Purpose of the Study:

  • To investigate centromere DNA alterations and their functional consequences in Systemic Sclerosis (SSc) fibroblasts.
  • To explore the relationship between centromere defects, chromosome instability, autoimmunity, and fibrosis in SSc.

Main Methods:

  • Analysis of centromeric DNA and protein localization in skin fibroblasts from SSc patients (diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc) subtypes).
  • Assessment of DNA damage, chromosome segregation, aneuploidy, and micronuclei formation.
  • Evaluation of cytoplasmic "leaking" of centromere proteins and their co-localization with MHC Class II molecules.
  • Correlation analysis with CENPA expression, cGAS-STING/IFN-β pathway activation, reactive oxygen species (ROS), and fibrosis markers.

Main Results:

  • SSc fibroblasts display significant alterations in centromeric DNA, DNA damage, and abnormal chromosome segregation.
  • Micronuclei formation is observed in all SSc types, with some losing centromere identity while retaining DNA sequences.
  • Cytoplasmic "leaking" of centromere proteins occurs in lcSSc fibroblasts, co-localizing with MHC Class II molecules and correlating with anti-centromere antibodies.
  • CENPA expression and micronuclei formation are strongly associated with cGAS-STING/IFN-β pathway activation, ROS, and fibrosis.

Conclusions:

  • Centromere defects and chromosome instability are prevalent in SSc fibroblasts.
  • These findings suggest a novel link between centromere alterations, SSc autoimmunity, and the development of fibrosis.
  • Targeting centromere integrity and associated pathways may offer new therapeutic strategies for SSc.

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