2. Academic Validation
  3. Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation

Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation

  • Haematologica. 2018 Jul;103(7):1110-1123. doi: 10.3324/haematol.2018.187708.
Yile Zhou 1 2,  Xiaomei Yan 2,  Xiaomin Feng 2,  Jiachen Bu 2 3,  Yunzhu Dong 2,  Peipei Lin 2,  Yoshihiro Hayashi 2,  Rui Huang 2,  Andre Olsson 4,  Paul R Andreassen 2,  H Leighton Grimes 4,  Qian-Fei Wang 3,  Tao Cheng 5,  Zhijian Xiao 5,  Jie Jin 6,  Gang Huang 7
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Division of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA.
  • 3 Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China.
  • 4 Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, OH, USA.
  • 5 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
  • 6 Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China gang.huang@cchmc.org jiej0503@zju.edu.cn.
  • 7 Division of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA gang.huang@cchmc.org jiej0503@zju.edu.cn.
PMID: 29650642 DOI: 10.3324/haematol.2018.187708
Abstract

SET domain containing 2 (Setd2), encoding a Histone Methyltransferase, is associated with many hematopoietic diseases when mutated. By generating a novel exon 6 conditional knockout mouse model, we describe an essential role of Setd2 in maintaining the adult hematopoietic stem cells. Loss of Setd2 results in leukopenia, anemia, and increased platelets accompanied by hypocellularity, erythroid dysplasia, and mild fibrosis in bone marrow. Setd2 knockout mice show significantly decreased hematopoietic stem and progenitor cells except for erythroid progenitors. Setd2 knockout hematopoietic stem cells fail to establish long-term bone marrow reconstitution after transplantation because of the loss of quiescence, increased Apoptosis, and reduced multiple-lineage terminal differentiation potential. Bioinformatic analysis revealed that the hematopoietic stem cells exit from quiescence and commit to differentiation, which lead to hematopoietic stem cell exhaustion. Mechanistically, we attribute an important Setd2 function in murine adult hematopoietic stem cells to the inhibition of the Nsd1/2/3 transcriptional complex, which recruits super elongation complex and controls RNA polymerase II elongation on a subset of target genes, including Myc Our results reveal a critical role of Setd2 in regulating quiescence and differentiation of hematopoietic stem cells through restricting the NSDs/SEC mediated RNA polymerase II elongation.

Figures
Products