title: Quantitative assessment of higher-order chromatin structure of the INK4/ARF locus in human senescent cells.
abstract: Somatic cells can be reset to oncogene-induced senescent (OIS) cells or induced pluripotent stem (iPS) cells by expressing specified factors. The INK4/ARF locus encodes p15(INK4b) , ARF, and p16(INK4a)  genes in human chromosome 9p21, the products of which are known as common key reprogramming regulators. Compared with growing fibroblasts, the CCCTC-binding factor CTCF is remarkably up-regulated in iPS cells with silencing of the three genes in the locus and is reversely down-regulated in OIS cells with high expression of p15(INK4b)  and p16(INK4a)  genes. There are at least three CTCF-enriched sites in the INK4/ARF locus, which possess chromatin loop-forming activities. These CTCF-enriched sites and the p16(INK4a)  promoter associate to form compact chromatin loops in growing fibroblasts, while CTCF depletion disrupts the loop structure. Interestingly, the loose chromatin structure is found in OIS cells. In addition, the INK4/ARF locus has an intermediate type of chromatin compaction in iPS cells. These results suggest that senescent cells have distinct higher-order chromatin signature in the INK4/ARF locus.
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Global Center of Excellence Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Hirosue
authors.forename: Ko
authors.initials: K
authors.lastname: Ishihara
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Takehisa
authors.initials: T
authors.lastname: Watanabe
authors.forename: Noriko
authors.initials: N
authors.lastname: Saitoh
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakamoto
authors.forename: Tamir
authors.initials: T
authors.lastname: Chandra
authors.forename: Masashi
authors.initials: M
authors.lastname: Narita
authors.forename: Masanori
authors.initials: M
authors.lastname: Shinohara
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D002843:Chromatin / Q000737:chemistry / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D006801:Humans
chemical_list: D002843:Chromatin; D019941:Cyclin-Dependent Kinase Inhibitor p16