期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34775-8
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资金
- Concerned Parents for AIDS Research (CPFA) [05-5089]
- Michigan Science Training Program [5T32GM007863-34]
- University of Michigan Cancer Biology Fellowship
- NIH/NIAMS [K24-AR063120-10]
- Rheumatology Research Foundation
- NIH [RO1-CA144043]
- Hormel Institute, the Rheumatology Research Foundation
- NIH/NCI [R21-CA259630]
- National Scleroderma Foundation
Skin fibrosis plays an important role in scleroderma. This study reveals significant alterations in centromeric DNA and cytoplasmic leaking of centromere proteins in fibroblasts from scleroderma patients. These abnormalities may be linked to genetic and epigenetic abnormalities at the centromere, chromosome instability, and autoimmune reactions.
Fibrosis of the skin plays an important role in scleroderma. Here the authors demonstrate genetic and epigenetic abnormalities at the centromere that affect the replication of the chromosomes, resulting in activation of pathways involved in inflammation and fibrosis Centromere defects in Systemic Sclerosis (SSc) have remained unexplored despite the fact that many centromere proteins were discovered in patients with SSc. Here we report that lesion skin fibroblasts from SSc patients show marked alterations in centromeric DNA. SSc fibroblasts also show DNA damage, abnormal chromosome segregation, aneuploidy (only in diffuse cutaneous (dcSSc)) and micronuclei (in all types of SSc), some of which lose centromere identity while retaining centromere DNA sequences. Strikingly, we find cytoplasmic leaking of centromere proteins in limited cutaneous SSc (lcSSc) fibroblasts. Cytoplasmic centromere proteins co-localize with antigen presenting MHC Class II molecules, which correlate precisely with the presence of anti-centromere antibodies. CENPA expression and micronuclei formation correlate highly with activation of the cGAS-STING/IFN-beta pathway as well as markers of reactive oxygen species (ROS) and fibrosis, ultimately suggesting a link between centromere alterations, chromosome instability, SSc autoimmunity, and fibrosis.
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