title: Ezh2 regulates the Lin28/let-7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells.
abstract: Fetal liver hematopoietic stem cells (HSCs) seed bone marrow (BM) and undergo reprograming into adult-type HSCs that are largely quiescent and restricted in their self-renewal activity. Here we report that in the absence of the polycomb-group gene Ezh2, a cohort of fetal-specific genes, including let-7 target genes, were activated in BM hematopoietic stem/progenitor cells (HSPCs), leading to acquisition of fetal phenotypes by BM HSPCs, such as enhanced self-renewal activity and production of fetal-type lymphocytes. The Lin28b/let-7 pathway determines developmentally timed changes in HSPC programs. Of note, many of the fetal-specific let-7 target genes, including Lin28, appear to be transcriptionally repressed by Ezh2-mediated H3K27me3 in BM HSPCs, and Ezh2 loss results in their ectopic expression, particularly in hematologic malignancies that develop in the absence of Ezh2. These findings suggest that Ezh2 cooperates with let-7 microRNAs in silencing the fetal gene signature in BM HSPCs and restricts their transformation.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; JST, CREST, Tokyo, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Oshima
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Nagisa
authors.initials: N
authors.lastname: Hasegawa
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; JST, CREST, Tokyo, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Mochizuki-Kashio
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Muto
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; JST, CREST, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyagi
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; JST, CREST, Tokyo, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Koide
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Yabata
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: George Russel
authors.initials: GR
authors.lastname: Wendt
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; JST, CREST, Tokyo, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Saraya
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; JST, CREST, Tokyo, Japan; College of Life Sciences, Inner Mongolia University, Hohhot, China.
authors.forename: Changshan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.affiliation: Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; JST, CREST, Tokyo, Japan. Electronic address: aiwama@faculty.chiba-u.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020868:Gene Silencing; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D063151:Polycomb Repressive Complex 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics*; D059467:Transcriptome
chemical_list: C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2