Project 4: Epigenetic control of human cell senescence

Project leader

Peter Adams, PhD.
Beatson Institute

Description

DNA methylation in senescence and aging

DNA methylation is an epigenetic mark crucial for regulation of gene expression and chromatin structure in mammalian cells. Hazel is interested in the role DNA methylation plays in senescence and aging. Using a variety of techniques, Hazel is studying DNA methylation changes in senescent cells with a human fibroblast model. Hazel finds a general loss of methylation in senescent cells, predominantly at repetitive regions of the genome typically associated with constitutive heterochromatin, suggesting a defect in the maintenance of these specialized structures. In parallel, DNA hypermethylation occurs at discrete genomic loci, particularly at CpG islands of genes. Hazel is currently investigating the impact of these alterations on senescent cells and how this may translate to organismal aging.

Maintenance of Chromatin structure of senescent cells

Senescence is an irreversible proliferation arrest thought to mediate tumour suppression, wound healing and tissue aging. This proliferative arrest is accompanied by profound changes in chromatin structure and metabolism including formation of senescence associated heterochromatin foci (SAHF), which are thought to repress expression of proliferation genes. Since senescent cells can persist in vitro and in vivo (e.g. human nevi) for long periods of time and chromatin is inherently dynamic, it raises the question – how is a stable chromatin structure maintained in non-proliferating cells? The mammalian HIRA/UBN1/CABIN1/ASF1a (HUCA) histone chaperone is implicated in chromatin structure regulation in non-proliferating cells. As a histone chaperone, HUCA preferentially deposits the histone variant H3.3 into chromatin. Taranjit is in process of defining this complex structurally and functionally. Ultimately, Taranjit will define the role of this complex in chromatin stability in non-proliferating cells, including senescent cells associated with aging.

Key Personnel

  • Hazel Cruickshanks
  • Taranjit Singh Rai
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