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      Ezh2 regulates the Lin28/let-7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells.

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          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.

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          Author and article information

          Journal
          Exp. Hematol.
          Experimental hematology
          Elsevier BV
          1873-2399
          0301-472X
          Apr 2016
          : 44
          : 4
          Affiliations
          [1 ] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan; JST, CREST, Tokyo, Japan.
          [2 ] Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
          [3 ] 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.
          [4 ] Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
          [5 ] Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
          [6 ] 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.
          Article
          S0301-472X(16)00002-3
          10.1016/j.exphem.2015.12.009
          26773568
          55179a2a-e3a6-45d4-9335-8683cd83c306
          History

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