title: FOXA1 mediates p16(INK4a) activation during cellular senescence.
abstract: Mechanisms governing the transcription of p16(INK4a), one of the master regulators of cellular senescence, have been extensively studied. However, little is known about chromatin dynamics taking place at its promoter and distal enhancer. Here, we report that Forkhead box A1 protein (FOXA1) is significantly upregulated in both replicative and oncogene-induced senescence, and in turn activates transcription of p16(INK4a) through multiple mechanisms. In addition to acting as a classic sequence-specific transcriptional activator, FOXA1 binding leads to a decrease in nucleosome density at the p16(INK4a) promoter in senescent fibroblasts. Moreover, FOXA1, itself a direct target of Polycomb-mediated repression, antagonizes Polycomb function at the p16(INK4a) locus. Finally, a systematic survey of putative FOXA1 binding sites in the p16(INK4a) genomic region revealed an ∼150 kb distal element that could loop back to the promoter and potentiate p16(INK4a) expression. Overall, our findings establish several mechanisms by which FOXA1 controls p16(INK4a) expression during cellular senescence.
authors: Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors: Qian
authors: Q
authors: Li
authors: Yu
authors: Y
authors: Zhang
authors: Jingxuan
authors: J
authors: Fu
authors: Limin
authors: L
authors: Han
authors: Lixiang
authors: L
authors: Xue
authors: Cuicui
authors: C
authors: Lv
authors: Pan
authors: P
authors: Wang
authors: Guodong
authors: G
authors: Li
authors: Tanjun
authors: T
authors: Tong
mesh_terms: D000367:Age Factors; D000818:Animals; D001483:Base Sequence; D016922:Cellular Senescence / Q000235:genetics*; D016000:Cluster Analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D006367:HeLa Cells; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D008954:Models, Biological; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha