Fulltext

Highly efficient Runx1 enhancer eR1-mediated genetic engineering for fetal, child and adult hematopoietic stem cells

Koh CP 1 , Bahirvani AG 2 , Wang CQ 3 , Yokomizo T 4 , Ng CEL 2 , Du L 2 Show all authors , Tergaonkar V 5 , Voon DC 6 , Kitamura H 2 , Hosoi H 7 , Sonoki T 8 , Michelle MMH 2 , Tan LJ 9 , Niibori-Nambu A 10 , Zhang Y 11 , Perkins AS 11 , Hossain Z 2 , Tenen DG 2 , Ito Y 2 , Venkatesh B 12 , Osato M 13

Affiliations 

  • 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117456, Singapore; Department of Biochemistry, Faculty of Medicine, Quest International University, Perak 30250, Malaysia
  • 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117456, Singapore
  • 3 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117456, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore
  • 4 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117456, Singapore; International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
  • 5 Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore
  • 6 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117456, Singapore; Cancer Research Institute, Kanazawa University, Ishikawa 920-1192, Japan; Institute for Frontier Science Initiative, Kanazawa University, Ishikawa 920-1192, Japan
  • 7 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117456, Singapore; Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
  • 8 Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
  • 9 Department of Forensic Medicine, Hospital Raja Permaisuri Bainun, Ipoh, Perak Daruk Ridzuan, Malaysia
  • 10 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117456, Singapore; Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Institute of Life Sciences, Kumamoto University, Kumamoto, Japan
  • 11 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States of America
  • 12 Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore. Electronic address: mcbbv@imcb.a-star.edu.sg
  • 13 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117456, Singapore; International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; Department of Pediatrics, National University of Singapore, Singapore 119228, Singapore. Electronic address: csimo@nus.edu.sg
Gene, 2023 Jan 30;851:147049.
PMID: 36384171 DOI: 10.1016/j.gene.2022.147049

Abstract

A cis-regulatory genetic element which targets gene expression to stem cells, termed stem cell enhancer, serves as a molecular handle for stem cell-specific genetic engineering. Here we show the generation and characterization of a tamoxifen-inducible CreERT2 transgenic (Tg) mouse employing previously identified hematopoietic stem cell (HSC) enhancer for Runx1, eR1 (+24 m). Kinetic analysis of labeled cells after tamoxifen injection and transplantation assays revealed that eR1-driven CreERT2 activity marks dormant adult HSCs which slowly but steadily contribute to unperturbed hematopoiesis. Fetal and child HSCs that are uniformly or intermediately active were also efficiently targeted. Notably, a gene ablation at distinct developmental stages, enabled by this system, resulted in different phenotypes. Similarly, an oncogenic Kras induction at distinct ages caused different spectrums of malignant diseases. These results demonstrate that the eR1-CreERT2 Tg mouse serves as a powerful resource for the analyses of both normal and malignant HSCs at all developmental stages.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

MeSH terms
Similar publications