Role of histone variants in aging and cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Aging is a universal process that affects all living organisms. While the cellular and organ-level disruptions caused by aging are well-documented, the specific nuclear events responsible for this phenomenon remain largely unknown. Cell growth and its division is tightly regulated by the nucleoprotein complex, chromatin, which undergoes various structural and functional changes during cellular aging. The factors mediating these alterations in chromatin structure during cellular senescence however is yet to be explored. In this project we focus on the centromeric chromatin which is responsible for the kinetochore formation and faithful cell segregation. The centromere is epigenetically marked by histone H3 variant, CENP-A which unlike the canonical histones are expressed in a replication independent manner. As cells cease to divide, we observe an increasing loss of the canonical histones along with the redistribution of repressive and accessible chromatin domains in aged cells. Through a proteomic analysis of heterochromatin and euchromatin fractions isolated from young and old human skin fibroblasts we found that aging not only led to the differential expression of several histone variants and chromatin associated proteins but also a change in their distribution pattern across the chromatin fractions. Interestingly, we also found that CENP-A, is reduced in the chromatin fractions of aged human cells which possibly contribute to the observed cell cycle arrest. This reduction of CENP-A in aged cells is accompanied by inactivation of centromeres epigenetically which results in mitotic defects. Furthermore, CENP-A reduction was also observed in aged fibroblasts obtained from otherwise healthy individuals. We also observed a substantial reduction in centromere transcription, prompting us to delve into the underlying molecular mechanism responsible for this downregulation. Through various cross-disciplinary approaches we elucidate an epigenetic pathway by which centromeric transcription is regulated. To further investigate this phenomenon and shed light on its implications for aging, we employed knockdown strategies targeting specific epigenetic regulators to reactivate centromeres in aged cells successfully. This study offers valuable insights into the mechanistic basis by which chromatin structure governs and influences the aging process through histone variants particularly that of centromeric histone variant. By expanding our understanding of these intricate processes, including why chromosome instability occurs during aging.