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

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.