title: DNA methylation status predicts cell type-specific enhancer activity.
abstract: Cell-selective glucocorticoid receptor (GR) binding to distal regulatory elements is associated with cell type-specific regions of locally accessible chromatin. These regions can either pre-exist in chromatin (pre-programmed) or be induced by the receptor (de novo). Mechanisms that create and maintain these sites are not well understood. We observe a global enrichment of CpG density for pre-programmed elements, and implicate their demethylated state in the maintenance of open chromatin in a tissue-specific manner. In contrast, sites that are actively opened by GR (de novo) are characterized by low CpG density, and form a unique class of enhancers devoid of suppressive effect of agglomerated methyl-cytosines. Furthermore, treatment with glucocorticoids induces rapid changes in methylation levels at selected CpGs within de novo sites. Finally, we identify GR-binding elements with CpGs at critical positions, and show that methylation can affect GR-DNA interactions in vitro. The findings present a unique link between tissue-specific chromatin accessibility, DNA methylation and transcription factor binding and show that DNA methylation can be an integral component of gene regulation by nuclear receptors.
authors.affiliation: Center for Cancer Research, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wiench
authors.forename: Sam
authors.initials: S
authors.lastname: John
authors.forename: Songjoon
authors.initials: S
authors.lastname: Baek
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Johnson
authors.forename: Myong-Hee
authors.initials: MH
authors.lastname: Sung
authors.forename: Thelma
authors.initials: T
authors.lastname: Escobar
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Simmons
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Pearce
authors.forename: Simon C
authors.initials: SC
authors.lastname: Biddie
authors.forename: Pete J
authors.initials: PJ
authors.lastname: Sabo
authors.forename: Robert E
authors.initials: RE
authors.lastname: Thurman
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Hager
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D051379:Mice; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: D002843:Chromatin; D011965:Receptors, Glucocorticoid; D004247:DNA