Page 25 - Hormel Report 2023

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Centromeres in Scleroderma
We have a special attention on the function of centromeres in
Scleroderma. The contribution of centromere defects to Scleroderma
remain unknown despite the fact that many of the centromere proteins
were discovered due to these patient-derived antibodies. Using novel
genetic and cytogenetic analysis we find that affected fibroblasts from
SSc patients show marked alterations in centromeric DNA regardless
of receiving treatment. Strikingly, we observed “leaking” of centromere
proteins from the nucleus into the cytoplasm in all limited cutaneous
Scleroderma patients who have anti-centromere antibodies. Scleroderma
fibroblasts showed abnormal chromosome segregation, with micronuclei
that activates the cGAS-STING pathway of autoimmunity. Surprisingly,
several micronuclei no longer recruit the centromere identity protein
CENPA, despite they still retain centromere sequences. Our studies reveal
that centromeric genomic instability and epigenetic defects may lead
to the pathogenesis of Scleroderma. As both centromere genetics and
epigenetics defects, together with an immune response to centromeres
is seen in Scleroderma patients, we are clarifying whether Scleroderma is a centromere disease with very promising findings. The projects are currently supported by the Scleroderma Foundation.
ORCID iD: https://orcid.org/0000-0002-6284-3359
Colocalization of cGAS to micronuclei in SSc fibroblasts. If analysis
of expression of cGAS (red) in SSc fibroblasts. Nuclei and micronuclei were stained in DAPI (blue). Micrographs showing cGAS expression and colocalization to micronuclei in an lcSSc patient.
PUBLICATION HIGHLIGHT:
• Paul, S., Kaplan, M. H., Khanna, D., McCourt, P. M., Saha, A. K., Tsou, P. S., Anand, M., Radecki, A., Mourad, M., Sawalha, A. H., Markovitz, D. M., & Contreras-Galindo, R. (2022). Centromere defects, chromosome instability, and cGAS-STING activation in systemic sclerosis. Nature Communications, 13(1), 16.
• Peixoto, E., Khan, A., Lewis, Z. A., Contreras-Galindo, R., & Czaja, W. (2022). The Chromatin Remodeler HELLS: A New Regulator in DNA Repair, Genome Maintenance, and Cancer. International Journal
of Molecular Sciences, 23(16), 12.