The senescent methylome and its relationship with cancer, ageing and germline genetic variation in humans.
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BACKGROUND: Cellular senescence is a stable arrest of proliferation and is considered a key component of processes associated with carcinogenesis and other ageing-related phenotypes. Here, we perform methylome analysis of actively dividing and deeply senescent normal human epithelial cells. RESULTS: We identify senescence-associated differentially methylated positions (senDMPs) from multiple experiments using cells from one donor. We find that human senDMP epigenetic signatures are positively and significantly correlated with both cancer and ageing-associated methylation dynamics. We also identify germline genetic variants, including those associated with the p16INK4A locus, which are associated with the presence of in vivo senDMP signatures. Importantly, we also demonstrate that a single senDMP signature can be effectively reversed in a newly-developed protocol of transient senescence reversal. CONCLUSIONS: The senDMP signature has significant potential for understanding some of the key (epi)genetic etiological factors that may lead to cancer and age-related diseases in humans.
Cyclin-Dependent Kinase Inhibitor p16
Polymorphism, Single Nucleotide
Published Version (Please cite this version)10.1186/s13059-015-0748-4
Publication InfoLowe, R; Overhoff, MG; Ramagopalan, SV; Garbe, JC; Koh, James; Stampfer, MR; ... Bishop, CL (2015). The senescent methylome and its relationship with cancer, ageing and germline genetic variation in humans. Genome Biol, 16. pp. 194. 10.1186/s13059-015-0748-4. Retrieved from http://hdl.handle.net/10161/15687.
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Assistant Professor of Surgery
The major effort in the lab is directed towards investigating how tumor-specific dysregulation of the pRB signaling pathway affects downstream gene expression and the cellular response to DNA damage. Four projects are currently underway. First, we are utilizing a modified chromatin immunoprecipitation approach to capture and identify genomic DNA target sequences conditionally associated with pRB-containing complexes recovered from intact chromatin in untransformed primary human cells. Se