Identification and characterization of novel histone modifications during cellular senescence

[摘要] Cellular senescence is a stable cell cycle arrest and can be triggered by various signals including telomere shortening, oncogenic activation and other stress activators. Senescence is accompanied by changes in the cellular organization, gene expression and induction of the secretome. It is established and maintained by at least two major tumor suppressor pathways, the p53-p21 and p16-pRB pathways. Senescence is now recognized as a potent barrier to tumor progression and is directly and indirectly linked to a large array of age-related pathologies. However theprecise molecular mechanisms of senescence, particularly how cells are driven into irreversible proliferation arrest, in not fully understood. It is well known thatwidespread changes in the chromatin structure of senescence contribute to the senescent phenotype.In line with this, the primary objective of this project is to understand how senescence is regulated by its chromatin structure. I have focussed on the identification and characterization of novel histone modifications that occur during senescence. Large-scale profiling of histone modifications was performed in replicatively senescent cells in comparison to proliferating cells. Candidate histone modifications were identified that alter during senescence from the screen. To our knowledge, this isthe first study to have implied a novel role for these histone modifications during senescence. Also a third histone modification, H4K16ac, was chosen for study basedon ChIP-seq observations made in the lab. The mark has also been extensively linked to cancer and aging.All together, work from this project imparts new knowledge on how certain novel histone modifications might regulate senescence via critical modulation of its chromatin structure and how they may impinge on senescence-associated effects such as ageing and cancer.

[发布机构] University:University of Glasgow;Department:Institute of Cancer Sciences

[关键词] senescence, chromatin, cancer, aging, histone.