title: Involvement of histone acetylation of Sox17 and Foxa2 promoters during mouse definitive endoderm differentiation revealed by microRNA profiling.
abstract: Generation of hepatocyte from embryonic stem cells (ESCs) holds great promise for hepatocyte replacement therapy to treat liver diseases. Achieving high efficiency of directed differentiation of ESCs to hepatocyte is of critical importance. Previously, Wnt3a has been reported to promote Activin A-induced human definitive endoderm (DE) differentiation, the early stage of hepatocyte differentiation. However, the underlying molecular mechanisms are not clear. Growing evidence demonstrated that microRNAs (miRNAs) are key regulators involved in various important biological processes including the regulation of stem cell differentiation. In the present study, we profiled genome wide miRNA expression during Wnt3a and Activin A induced mouse DE differentiation. We uncovered distinct miRNA expression patterns during DE differentiation with the identification of a subset of miRNAs whose expression is synergistically regulated by Wnt3a/Activin A treatment at different stages of DE differentiation. Forced expression of a pool of such synergistically regulated miRNAs alone could partially promote DE differentiation, indicating a regulatory role of them. Using TargetScan and GeneGO pathway analyses, the synergistically regulated miRNAs are predicted to regulate key pathways involved in DE differentiation; among them includes the regulation of histone acetylation. Consistently, Wnt3a and Activin A treatment increased global histone acetylation which can be partially mimicked by over expression of the pooled miRNAs. Chromatin IP (ChIP) experiments demonstrated that the promoter regions of Sox17 and Foxa2 are subjected to histone acetylation regulation. Administration of Hdac inhibitors greatly augmented DE differentiation. Our data uncovered a novel epigenetic mechanism of Wnt3a and Activin A induced DE differentiation, whereby the treatment of growth factors induced histone acetylation at least in part by the regulation of miRNA expression.
authors: China Novartis Institutes for BioMedical Research, Shanghai, China.
authors: Shijun
authors: S
authors: Fu
authors: Qi
authors: Q
authors: Fei
authors: Hua
authors: H
authors: Jiang
authors: Shannon
authors: S
authors: Chuai
authors: Song
authors: S
authors: Shi
authors: Wen
authors: W
authors: Xiong
authors: Lei
authors: L
authors: Jiang
authors: Chris
authors: C
authors: Lu
authors: Peter
authors: P
authors: Atadja
authors: En
authors: E
authors: Li
authors: Jianyong
authors: J
authors: Shou
mesh_terms: D000107:Acetylation / Q000187:drug effects; D028341:Activins / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004707:Endoderm / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D024002:HMGB Proteins / Q000235:genetics*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D055760:SOXF Transcription Factors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D060509:Wnt3A Protein / Q000494:pharmacology
chemical_list: D015415:Biomarkers; C496503:Foxa2 protein, mouse; D024002:HMGB Proteins; D006657:Histones; D006877:Hydroxamic Acids; D035683:MicroRNAs; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; D060509:Wnt3A Protein; C422405:activin A; D028341:Activins; D051542:Hepatocyte Nuclear Factor 3-beta; C012589:trichostatin A; D006655:Histone Deacetylases