title: Bivalent Regions of Cytosine Methylation and H3K27 Acetylation Suggest an Active Role for DNA Methylation at Enhancers.
abstract: The role of cytosine methylation in the structure and function of enhancers is not well understood. In this study, we investigate the role of DNA methylation at enhancers by comparing the epigenomes of the HCT116 cell line and its highly demethylated derivative, DKO1. Unlike promoters, a portion of regular and super- or stretch enhancers show active H3K27ac marks co-existing with extensive DNA methylation, demonstrating the unexpected presence of bivalent chromatin in both cultured and uncultured cells. Furthermore, our findings also show that bivalent regions have fewer nucleosome-depleted regions and transcription factor-binding sites than monovalent regions. Reduction of DNA methylation genetically or pharmacologically leads to a decrease of the H3K27ac mark. Thus, DNA methylation plays an unexpected dual role at enhancer regions, being anti-correlated focally at transcription factor-binding sites but positively correlated globally with the active H3K27ac mark to ensure structural enhancer integrity.
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Charlet
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Duymich
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Fides D
authors.initials: FD
authors.lastname: Lay
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Kamilla
authors.initials: K
authors.lastname: Mundbjerg
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
authors.forename: Karina
authors.initials: K
authors.lastname: Dalsgaard Sørensen
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: gliang@usc.edu.
authors.forename: Gangning
authors.initials: G
authors.lastname: Liang
authors.affiliation: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Biochemistry & Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address: pjones@med.usc.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D042002:Chromatin Assembly and Disassembly; D003596:Cytosine; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D045325:HCT116 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011499:Protein Processing, Post-Translational; D013997:Time Factors
chemical_list: D006657:Histones; D003596:Cytosine