title: Pluripotency factors and Polycomb Group proteins repress aryl hydrocarbon receptor expression in murine embryonic stem cells.
abstract: The aryl hydrocarbon receptor (AHR) is a transcription factor and environmental sensor that regulates expression of genes involved in drug-metabolism and cell cycle regulation. Chromatin immunoprecipitation analyses, Ahr ablation in mice and studies with orthologous genes in invertebrates suggest that AHR may also play a significant role in embryonic development. To address this hypothesis, we studied the regulation of Ahr expression in mouse embryonic stem cells and their differentiated progeny. In ES cells, interactions between OCT3/4, NANOG, SOX2 and Polycomb Group proteins at the Ahr promoter repress AHR expression, which can also be repressed by ectopic expression of reprogramming factors in hepatoma cells. In ES cells, unproductive RNA polymerase II binds at the Ahr transcription start site and drives the synthesis of short abortive transcripts. Activation of Ahr expression during differentiation follows from reversal of repressive marks in Ahr promoter chromatin, release of pluripotency factors and PcG proteins, binding of Sp factors, establishment of histone marks of open chromatin, and engagement of active RNAPII to drive full-length RNA transcript elongation. Our results suggest that reversible Ahr repression in ES cells holds the gene poised for expression and allows for a quick switch to activation during embryonic development.
authors: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, USA.
authors: Chia-I
authors: CI
authors: Ko
authors: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, USA.
authors: Qin
authors: Q
authors: Wang
authors: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, USA.
authors: Yunxia
authors: Y
authors: Fan
authors: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, USA.
authors: Ying
authors: Y
authors: Xia
authors: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, USA. Electronic address: Alvaro.Puga@uc.edu.
authors: Alvaro
authors: A
authors: Puga
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D051705:Sp3 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D002843:Chromatin; D006657:Histones; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D063146:Polycomb-Group Proteins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051705:Sp3 Transcription Factor; D012319:RNA Polymerase II
keywords: 2,3,7,8-tetrachlorodibenzo-p-dioxin; AHR; AHR response element; ARNT; Ah receptor nuclear translocator; AhRE; CTD; ChIP; EB; EMT; ESC; EZH2; H3K27ac; H3K27me3/2/1; H3K36me3; H3K4me3/2/1; H3K9ac; H3K9me3/2/1; H3ac; HMT; ICM; KDM6A/B; KO; MET; MLL; OCT3/4, SOX2, KLF4, MYC; OSKM; PRC1/2; PcG; Polycomb Group proteins; Polycomb repressive complexes 1 and 2; RING1B; RNA polymerase II; RNA polymerase II hyperphosphorylated in CTD serine-5 and serine-2; RNA polymerase II phosphorylated in CTD serine-5 but not serine-2; RNAPII; RNAPII (S5p(+)S2p(+)); RNAPII (S5p(+)S2p(−)); SUZ12; TCDD; TES; TSS; Trithorax Group proteins; TxG; acetylated histone H3; acetylated lysine-27 of histone H3; acetylated lysine-9 of histone H3; aryl hydrocarbon receptor; bHLH/PAS; basic helix–loop–helix/Per-ARNT-Sim; carboxyl-terminal repeat domain; chromatin immunoprecipitation; embryoid bodies; embryonic stem cells; enhancer of zeste homolog 2; epithelial-to-mesenchymal transition; histone methyltransferase; iPSC; induced pluripotent stem cells; inner-cell-mass; knock out; lysine demethylase 6A and 6B; mesenchymal-to-epithelial transition; myeloid/lymphoid or mix-lineage leukemia; ring finger protein 1B; suppressor of zeste 12 homolog; transcription end site; transcription start site; tri-methylated lysine-36 of histone H3; tri/di/mono-methylated lysine-27 of histone H3; tri/di/mono-methylated lysine-4 of histone H3; tri/di/mono-methylated lysine-9 of histone H3