title: Hmga2 is a direct target gene of RUNX1 and regulates expansion of myeloid progenitors in mice.
abstract: RUNX1 is a master transcription factor in hematopoiesis and mediates the specification and homeostasis of hematopoietic stem and progenitor cells (HSPCs). Disruptions in RUNX1 are well known to lead to hematologic disease. In this study, we sought to identify and characterize RUNX1 target genes in HSPCs by performing RUNX1 chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) using a murine HSPC line and complementing this data with our previously described gene expression profiling of primary wild-type and RUNX1-deficient HSPCs (Lineage(-)/cKit(+)/Sca1(+)). From this analysis, we identified and confirmed that Hmga2, a known oncogene, as a direct target of RUNX1. Hmga2 was strongly upregulated in RUNX1-deficient HSPCs, and the promoter of Hmga2 was responsive in a cell-type dependent manner upon coexpression of RUNX1. Conditional Runx1 knockout mice exhibit expansion of their HSPCs and myeloid progenitors as hallmark phenotypes. To further validate and establish that Hmga2 plays a role in inducing HSPC expansion, we generated mouse models of HMGA2 and RUNX1 deficiency. Although mice lacking both factors continued to display higher frequencies of HSPCs, the expansion of myeloid progenitors was effectively rescued. The data presented here establish Hmga2 as a transcriptional target of RUNX1 and a critical regulator of myeloid progenitor expansion.
authors.affiliation: Moores UCSD Cancer Center, University of California-San Diego, La Jolla, CA;
authors.forename: Kentson
authors.initials: K
authors.lastname: Lam
authors.affiliation: Moores UCSD Cancer Center, University of California-San Diego, La Jolla, CA;
authors.forename: Alexander
authors.initials: A
authors.lastname: Muselman
authors.affiliation: Moores UCSD Cancer Center, University of California-San Diego, La Jolla, CA;
authors.forename: Randal
authors.initials: R
authors.lastname: Du
authors.affiliation: Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; and.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Harada
authors.affiliation: Moores UCSD Cancer Center, University of California-San Diego, La Jolla, CA; Departments of Pathology and Division of Biological Sciences, University of California-San Diego, La Jolla, CA.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Scholl
authors.affiliation: Moores UCSD Cancer Center, University of California-San Diego, La Jolla, CA;
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Moores UCSD Cancer Center, University of California-San Diego, La Jolla, CA;
authors.forename: Shinobu
authors.initials: S
authors.lastname: Matsuura
authors.affiliation: Moores UCSD Cancer Center, University of California-San Diego, La Jolla, CA;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Weng
authors.affiliation: Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; and.
authors.forename: Hironori
authors.initials: H
authors.lastname: Harada
authors.affiliation: Moores UCSD Cancer Center, University of California-San Diego, La Jolla, CA; Departments of Pathology and Division of Biological Sciences, University of California-San Diego, La Jolla, CA.
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D005786:Gene Expression Regulation; D025743:HMGA2 Protein / Q000378:metabolism*; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000166:cytology*; D041681:NIH 3T3 Cells; D010641:Phenotype; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D025743:HMGA2 Protein; C493726:Runx1 protein, mouse; D014157:Transcription Factors