Disparate chromatin landscapes and kinetics of inactivation impact differential regulation of p53 target genes.
The p53 transcription factor regulates the expression of genes involved in cellular responses to stress, including cell cycle arrest and apoptosis. The p53 transcriptional program is extremely malleable, with target gene expression varying in a stress- and cell type-specific fashion. The molecular mechanisms underlying differential p53 target gene expression remain elusive. Here we provide evidence for gene-specific mechanisms affecting expression of three important p53 target genes. First we show that transcription of the apoptotic gene PUMA is regulated through intragenic chromatin boundaries, as revealed by distinct histone modification territories that correlate with binding of the insulator factors CTCF, Cohesins and USF1/2. Interestingly, this mode of regulation produces an evolutionary conserved long non-coding RNA of unknown function. Second, we demonstrate that the kinetics of transcriptional competence of the cell cycle arrest gene p21 and the apoptotic gene FAS are markedly different in vivo, as predicted by recent biochemical dissection of their core promoter elements in vitro. After a pulse of p53 activity in cells, assembly of the transcriptional apparatus on p21 is rapidly reversed, while FAS transcriptional activation is more sustained. Collectively these data add to a growing list of p53-autonomous mechanisms that impact differential regulation of p53 target genes.
Gomes
Nathan P
NP
Howard Hughes Medical Institute, Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA.
Espinosa
Joaquín M
JM
D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D022661:RNA, Untranslated / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism; D000097722:Cohesins
D051017:Apoptosis Regulatory Proteins; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D011518:Proto-Oncogene Proteins; D022661:RNA, Untranslated; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D000097722:Cohesins; C438378:BBC3 protein, human; C000619697:CTCF protein, human; C491901:FAS protein, human
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