Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island.
Epigenetic silencing of tumor suppressor genes is generally thought to involve DNA cytosine methylation, covalent modifications of histones, and chromatin compaction. Here, we show that silencing of the three transcription start sites in the bidirectional MLH1 promoter CpG island in cancer cells involves distinct changes in nucleosomal occupancy. Three nucleosomes, almost completely absent from the start sites in normal cells, are present on the methylated and silenced promoter, suggesting that epigenetic silencing may be accomplished by the stable placement of nucleosomes into previously vacant positions. Activation of the promoter by demethylation with 5-aza-2'-deoxycytidine involves nucleosome eviction. Epigenetic silencing of tumor suppressor genes may involve heritable changes in nucleosome occupancy enabled by cytosine methylation.
Lin
Joy C
JC
Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Jeong
Shinwu
S
Liang
Gangning
G
Takai
Daiya
D
Fatemi
Merhnaz
M
Tsai
Yvonne C
YC
Egger
Gerda
G
Gal-Yam
Einav Nili
EN
Jones
Peter A
PA
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D003850:Deoxyribonuclease I / Q000378:metabolism; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008957:Models, Genetic; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D009707:Nucleosomes / Q000378:metabolism*; D011401:Promoter Regions, Genetic
D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D009707:Nucleosomes; D003596:Cytosine; D003850:Deoxyribonuclease I; D000070957:MutL Protein Homolog 1