title: Plant Homeo Domain Finger Protein 8 Regulates Mesodermal and Cardiac Differentiation of Embryonic Stem Cells Through Mediating the Histone Demethylation of pmaip1.
abstract: Histone demethylases have emerged as key regulators of biological processes. The H3K9me2 demethylase plant homeo domain finger protein 8(PHF8), for example, is involved in neuronal differentiation, but its potential function in the differentiation of embryonic stem cells (ESCs) to cardiomyocytes is poorly understood. Here, we explored the role of PHF8 during mesodermal and cardiac lineage commitment of mouse ESCs (mESCs). Using a phf8 knockout (ph8(-/Y) ) model, we found that deletion of phf8 in ESCs did not affect self-renewal, proliferation or early ectodermal/endodermal differentiation, but it did promote the mesodermal lineage commitment with the enhanced cardiomyocyte differentiation. The effects were accompanied by a reduction in apoptosis through a caspase 3-independent pathway during early ESC differentiation, without significant differences between differentiating wide-type (ph8(+/Y) ) and ph8(-/Y) ESCs in cell cycle progression or proliferation. Functionally, PHF8 promoted the loss of a repressive mark H3K9me2 from the transcription start site of a proapoptotic gene pmaip1 and activated its transcription. Furthermore, knockdown of pmaip1 mimicked the phenotype of ph8(-/Y) by showing the decreased apoptosis during early differentiation of ESCs and promoted mesodermal and cardiac commitment, while overexpression of pmaip1 or phf8 rescued the phenotype of ph8(-/Y) ESCs by increasing the apoptosis and weakening the mesodermal and cardiac differentiation. These results reveal that the histone demethylase PHF8 regulates mesodermal lineage and cell fate decisions in differentiating mESCs through epigenetic control of the gene critical to programmed cell death pathways. Stem Cells 2016;34:1527-1540.
authors: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) University of Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Yan
authors: Y
authors: Tang
authors: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) University of Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Ya-Zhen
authors: YZ
authors: Hong
authors: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) University of Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Hua-Jun
authors: HJ
authors: Bai
authors: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) University of Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Qiang
authors: Q
authors: Wu
authors: State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.
authors: Charlie Degui
authors: CD
authors: Chen
authors: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) University of Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Jing-Yu
authors: JY
authors: Lang
authors: LKS Faculty of Medicine, Department of Physiology and Stem Cell and Regenerative Medicine Consortium, School of Biomedical Sciences, Jockey Club Building for Interdisciplinary Research, University of Hong Kong, Hong Kong, SAR China.
authors: Kenneth R
authors: KR
authors: Boheler
authors: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) University of Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Second Affiliated Hospital, Zhejiang University, Hangzhou, China.
authors: Huang-Tian
authors: HT
authors: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D000073398:Demethylation; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D006657:Histones; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D056466:Histone Demethylases; C553256:PHF8 protein, mouse
keywords: Apoptosis; Embryonic stem cells; Histone demethylas; Mesodermal and cardiac differentiation; Phorbol-12-myristate-13-acetate-induced protein 1; Plant homeo domain finger protein 8