title: The EP300, KDM5A, KDM6A and KDM6B chromatin regulators cooperate with KLF4 in the transcriptional activation of POU5F1.
abstract: POU5F1 is essential for maintaining pluripotency in embryonic stem cells (ESCs). It has been reported that the constitutive activation of POU5F1 is sustained by the core transcriptional regulatory circuitry in ESCs; however, the means by which POU5F1 is epigenetically regulated remains enigmatic. In this study a fluorescence-based reporter system was used to monitor the interplay of 5 reprogramming-associated TFs and 17 chromatin regulators in the transcription of POU5F1. We show the existence of a stoichiometric effect for SOX2, POU5F1, NANOG, MYC and KLF4, in regulating POU5F1 transcription. Chromatin regulators EP300, KDM5A, KDM6A and KDM6B cooperate with KLF4 in promoting the transcription of POU5F1. Moreover, inhibiting HDAC activities induced the expression of Pou5f1 in mouse neural stem cells (NSCs) in a spatial- and temporal- dependent manner. Quantitative chromatin immunoprecipitation-PCR (ChIP-qPCR) shows that treatment with valproic acid (VPA) increases the recruitment of Kdm5a and Kdm6a to proximal promoter (PP) and proximal enhancer (PE) of Pou5f1 whereas enrichment of Ep300 and Kdm6b was seen in PP but not PE of Pou5f1 promoter. These findings reveal the interplay between the chromatin regulators and histone modifications in the expression of POU5F1.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Wan-Ping
authors.initials: WP
authors.lastname: Wang
authors.forename: Tsai-Yu
authors.initials: TY
authors.lastname: Tzeng
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Wang
authors.forename: Don-Ching
authors.initials: DC
authors.lastname: Lee
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Lin
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Wu
authors.forename: Yen-Po
authors.initials: YP
authors.lastname: Chen
authors.forename: Ing-Ming
authors.initials: IM
authors.lastname: Chiu
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chi
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D056466:Histone Demethylases / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D000071317:Nanog Homeobox Protein; D058953:Neural Stem Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D056485:Retinoblastoma-Binding Protein 2 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C070050:KDM5A protein, human; C523998:KDM6A protein, human; C524220:KDM6B protein, human; D056485:Retinoblastoma-Binding Protein 2; D050881:E1A-Associated p300 Protein