INSIGHTS INTO AGING AND LIPODYSTROPHY FROM PROGEROID SYNDROME EPIGENETICS

Abstract

Progeroid syndromes are characterized by an accelerated form of aging compared to normal aging. They provide great models for a better understanding of the pathobiology of aging. Through this thesis, two congenital progeroid syndromes were studied from an epigenetic perspective, Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2 or CGL2) and Hutchinson-Gilford Progeria Syndrome (HGPS). Both are extremely rare genetic disorders and are characterized by premature and accelerated aging beginning in childhood. CGL2 patients display characteristic progeroid features and suffer from type 2 diabetes, insulin resistance, and fatty liver. Genome-wide DNA methylation levels were measured in CGL2 patients with BSCL2 mutations to study epigenetic age acceleration and DNA methylation alterations using the Infinium Methylation Epic array. This analysis revealed significant age acceleration in the blood DNA of CGL2 patients using both first- and second-generation epigenetic clocks. A shortened lifespan of Caenorhabditis elegans was also observed following the knockdown of the BSCL2 homolog seip-1 on a daf-16/forkhead box, class O mutant background. Furthermore, a significant hypomethylation in the promoter of the dual specificity phosphatase 22 gene (DUSP22) could be observed. For HGPS, the methylation analysis was performed on the blood DNA of 15 patients with progeroid laminopathies including 8 patients with classical HGPS and 7 progeroid laminopathy patients with the non-classical LMNA mutations. This analysis revealed DNA methylation alterations at 61 CpG sites as well as 32 significant regions following a 5 Kb tiling analysis. In addition, significant methylation differences in classic HGPS were detected when specifically looking at probes overlapping solo-WCGW partially methylated domains. In conclusion, characterizing epigenetically altered sites unveils new genes and pathways that can potentially contribute to the pathogenesis of progeroid laminopathy or CGL2, and can provide valuable insights into understanding the biology of aging.

Date of Award	2023
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences