Transcription factor interactions and chromatin modifications associated with p53-mediated, developmental repression of the alpha-fetoprotein gene.
We performed chromatin immunoprecipitation (ChIP) analyses of developmentally staged solid tissues isolated from wild-type and p53-null mice to determine specific histone N-terminal modifications, histone-modifying proteins, and transcription factor interactions at the developmental repressor region (-850) and core promoter of the hepatic tumor marker alpha-fetoprotein (AFP) gene. Both repression of AFP during liver development and silencing in the brain, where AFP is never expressed, are associated with dimethylation of histone H3 lysine 9 (DiMetH3K9) and the presence of heterochromatin protein 1 (HP1). These heterochromatic markers remain localized to AFP during developmental repression but spread to the upstream albumin gene during silencing. Developmentally regulated decreases in levels of acetylated H3 (AcH3K9) and H4 (AcH4) and of di- and trimethylated H3K4 (DiMetH3K4 and TriMetH3K4) occur at both the core promoter and distal repressor regions of AFP. Hepatic expression of AFP correlates with FoxA interaction at the repressor region and the binding of RNA polymerase II and TATA-binding protein to the core promoter. p53 acts as a developmental repressor of AFP in the liver by binding to chromatin, excluding FoxA interaction and targeting mSin3A/HDAC1 to the distal repressor region. p53-null mice exhibit developmentally delayed AFP repression, concomitant with acetylation of H3K9, methylation of H3K4, and loss of DiMetH3K9, mSin3A/HDAC1, and HP1 interactions.
Nguyen
Thi T
TT
Department of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biological Sciences, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Cho
Kyucheol
K
Stratton
Sabrina A
SA
Barton
Michelle Craig
MC
D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D051541:Hepatocyte Nuclear Factor 3-alpha; D022781:Hepatocytes / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000509:alpha-Fetoproteins / Q000235:genetics*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D006570:Heterochromatin; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000509:alpha-Fetoproteins; D000090266:Chromobox Protein Homolog 5
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