title: Transient ectopic expression of the histone demethylase JMJD3 accelerates the differentiation of human pluripotent stem cells.
abstract: Harnessing epigenetic regulation is crucial for the efficient and proper differentiation of pluripotent stem cells (PSCs) into desired cell types. Histone H3 lysine 27 trimethylation (H3K27me3) functions as a barrier against cell differentiation through the suppression of developmental gene expression in PSCs. Here, we have generated human PSC (hPSC) lines in which genome-wide reduction of H3K27me3 can be induced by ectopic expression of the catalytic domain of the histone demethylase JMJD3 (called JMJD3c). We found that transient, forced demethylation of H3K27me3 alone triggers the upregulation of mesoendodermal genes, even when the culture conditions for the hPSCs are not changed. Furthermore, transient and forced expression of JMJD3c followed by the forced expression of lineage-defining transcription factors enabled the hPSCs to activate tissue-specific genes directly. We have also shown that the introduction of JMJD3c facilitates the differentiation of hPSCs into functional hepatic cells and skeletal muscle cells. These results suggest the utility of the direct manipulation of epigenomes for generating desired cell types from hPSCs for cell transplantation therapy and platforms for drug screenings.
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan akiyama617@keio.jp ko.minoru@keio.jp.
authors: Tomohiko
authors: 0000-0002-1238-8095
authors: T
authors: Akiyama
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan.
authors: Shunichi
authors: S
authors: Wakabayashi
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan.
authors: Atsumi
authors: A
authors: Soma
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan.
authors: Saeko
authors: S
authors: Sato
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan.
authors: Yuhki
authors: Y
authors: Nakatake
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan.
authors: Mayumi
authors: M
authors: Oda
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan.
authors: Miyako
authors: M
authors: Murakami
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan.
authors: Miki
authors: M
authors: Sakota
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan.
authors: Nana
authors: N
authors: Chikazawa-Nohtomi
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan.
authors: Shigeru B H
authors: 0000-0003-1913-6357
authors: SB
authors: Ko
authors: Department of Systems Medicine, Keio University School of Medicine, Tokyo 160, Japan akiyama617@keio.jp ko.minoru@keio.jp.
authors: Minoru S H
authors: 0000-0002-3530-3015
authors: MS
authors: Ko
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D000066630:Ectopic Gene Expression / Q000235:genetics / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D000072041:PAX3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051763:PAX7 Transcription Factor / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; C495195:KDM1A protein, human
keywords: Hepatocytes; Histone demethylase; Human pluripotent stem cells; JMJD3; KDM6B; Skeletal muscle