title: Epigenetic Variation between Human Induced Pluripotent Stem Cell Lines Is an Indicator of Differentiation Capacity.
abstract: Variation in the differentiation capacity of induced pluripotent stem cells (iPSCs) to specific lineages is a significant concern for their use in clinical applications and disease modeling. To identify factors that affect differentiation capacity, we performed integration analyses between hematopoietic differentiation performance and molecular signatures such as gene expression, DNA methylation, and chromatin status, using 35 human iPSC lines and four ESC lines. Our analyses revealed that hematopoietic commitment of PSCs to hematopoietic precursors correlates with IGF2 expression level, which in turn depends on signaling-dependent chromatin accessibility at mesendodermal genes. Maturation capacity for conversion of PSC-derived hematopoietic precursors to mature blood associates with the amount and pattern of DNA methylation acquired during reprogramming. Our study therefore provides insight into the molecular features that determine the differential capacities seen among human iPSC lines and, through the predictive potential of this information, highlights a way to select optimal iPSCs for clinical applications.
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nishizawa
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Chonabayashi
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nomura
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Inagaki
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Ikue
authors.initials: I
authors.lastname: Takei
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Oishi
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tanabe
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ohnuki
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Hidaka
authors.initials: H
authors.lastname: Yokota
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Koyanagi-Aoi
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okita
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8501, Japan; Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. Electronic address: yoshinor@cira.kyoto-u.ac.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yoshida
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D002843:Chromatin / Q000737:chemistry; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D053263:Gene Regulatory Networks; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D016513:Mice, SCID; D015398:Signal Transduction / Q000235:genetics; D033581:Stem Cell Transplantation; D000070584:Tripartite Motif Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D000070584:Tripartite Motif Proteins; D028341:Activins; D005346:Fibroblast Growth Factors; D007335:Insulin-Like Growth Factor II
keywords: DNA methylation; chromatin accessibility; hematopoietic differentiation; human induced pluripotent stem cell; insulin-like growth factor 2; mRNA microarray; reprogramming-related DNA methylation