title: The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype.
abstract: Most colorectal cancers (CRCs) containing activated BRAF (BRAF[V600E]) have a CpG island methylator phenotype (CIMP) characterized by aberrant hypermethylation of many genes, including the mismatch repair gene MLH1. MLH1 silencing results in microsatellite instability and a hypermutable phenotype. Through an RNAi screen, here we identify the transcriptional repressor MAFG as the pivotal factor required for MLH1 silencing and CIMP in CRCs containing BRAF(V600E). In BRAF-positive human CRC cell lines and tumors, MAFG is bound at the promoters of MLH1 and other CIMP genes, and recruits a corepressor complex that includes its heterodimeric partner BACH1, the chromatin remodeling factor CHD8, and the DNA methyltransferase DNMT3B, resulting in hypermethylation and transcriptional silencing. BRAF(V600E) increases BRAF/MEK/ERK signaling resulting in phosphorylation and elevated levels of MAFG, which drives DNA binding. Analysis of transcriptionally silenced CIMP genes in KRAS-positive CRCs indicates that different oncoproteins direct the assembly of distinct repressor complexes on common promoters.
authors.affiliation: Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Minggang
authors.initials: M
authors.lastname: Fang
authors.affiliation: Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Ou
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Hutchinson
authors.affiliation: Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA; Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: michael.green@umassmed.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051259:MafG Transcription Factor / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009374:Neoplasms, Experimental; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050976:Basic-Leucine Zipper Transcription Factors; D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D051259:MafG Transcription Factor; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins; D048493:Proto-Oncogene Proteins B-raf; D012097:Repressor Proteins; D014157:Transcription Factors; D000097584:DNA Methyltransferase 3B; C102108:BACH1 protein, human; C523331:CHD8 protein, human; C103944:MAFG protein, human; C501486:MLH1 protein, human; C482119:BRAF protein, human