The role of DNA methylation in directing the functional organization of the cancer epigenome.
The holistic role of DNA methylation in the organization of the cancer epigenome is not well understood. Here we perform a comprehensive, high-resolution analysis of chromatin structure to compare the landscapes of HCT116 colon cancer cells and a DNA methylation-deficient derivative. The NOMe-seq accessibility assay unexpectedly revealed symmetrical and transcription-independent nucleosomal phasing across active, poised, and inactive genomic elements. DNA methylation abolished this phasing primarily at enhancers and CpG island (CGI) promoters, with little effect on insulators and non-CGI promoters. Abolishment of DNA methylation led to the context-specific reestablishment of the poised and active states of normal colon cells, which were marked in methylation-deficient cells by distinct H3K27 modifications and the presence of either well-phased nucleosomes or nucleosome-depleted regions, respectively. At higher-order genomic scales, we found that long, H3K9me3-marked domains had lower accessibility, consistent with a more compact chromatin structure. Taken together, our results demonstrate the nuanced and context-dependent role of DNA methylation in the functional, multiscale organization of cancer epigenomes.
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA; Program in Genetic, Molecular and Cellular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA;
Fides D
FD
Lay
Program in Genetic, Molecular and Cellular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA; USC Epigenome Center, University of Southern California, Los Angeles, California 90033, USA;
Yaping
Y
Liu
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA;
Theresa K
TK
Kelly
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA;
Heather
H
Witt
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA;
Peggy J
PJ
Farnham
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA; Van Andel Institute, Grand Rapids, Michigan 49503, USA; benjamin.berman@cshs.org pjones@med.usc.edu.
Peter A
PA
Jones
USC Epigenome Center, University of Southern California, Los Angeles, California 90033, USA; Department of Preventive Medicine, University of Southern California, Los Angeles, California 90033, USA benjamin.berman@cshs.org pjones@med.usc.edu.
Benjamin P
BP
Berman
D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D045325:HCT116 Cells; D006657:Histones / Q000235:genetics; D006801:Humans; D009707:Nucleosomes / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D000097584:DNA Methyltransferase 3B
D002843:Chromatin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D006657:Histones; D009707:Nucleosomes; D000097584:DNA Methyltransferase 3B