title: A Runx1-Smad6 rheostat controls Runx1 activity during embryonic hematopoiesis.
abstract: The oncogenic transcription factor Runx1 is required for the specification of definitive hematopoietic stem cells (HSC) in the developing embryo. The activity of this master regulator is tightly controlled during development. The transcription factors that upregulate the expression of Runx1 also upregulate the expression of Smad6, the inhibitory Smad, which controls Runx1 activity by targeting it to the proteasome. Here we show that Runx1, in conjunction with Fli1, Gata2, and Scl, directly regulates the expression of Smad6 in the aorta-gonad-mesonephros (AGM) region in the developing embryo, where HSCs originate. Runx1 regulates Smad6 activity via a novel upstream enhancer, and Runx1 null embryos show reduced Smad6 transcripts in the yolk-sac and c-Kit-positive fetal liver cells. By directly regulating the expression of Smad6, Runx1 sets up a functional rheostat to control its own activity. The perturbation of this rheostat, using a proteasomal inhibitor, results in an increase in Runx1 and Smad6 levels that can be directly attributed to increased Runx1 binding to tissue-specific regulatory elements of these genes. Taken together, we describe a scenario in which a key hematopoietic transcription factor controls its own expression levels by transcriptionally controlling its controller.
authors.affiliation: Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Kathy
authors.initials: K
authors.lastname: Knezevic
authors.forename: Thomas
authors.initials: T
authors.lastname: Bee
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Wilson
authors.forename: Mary E
authors.initials: ME
authors.lastname: Janes
authors.forename: Sarah
authors.initials: S
authors.lastname: Kinston
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Polderdijk
authors.forename: Anja
authors.initials: A
authors.lastname: Kolb-Kokocinski
authors.forename: Katrin
authors.initials: K
authors.lastname: Ottersbach
authors.forename: Niv
authors.initials: N
authors.lastname: Pencovich
authors.forename: Yoram
authors.initials: Y
authors.lastname: Groner
authors.forename: Marella
authors.initials: M
authors.lastname: de Bruijn
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012045:Regulatory Sequences, Nucleic Acid; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D051905:Smad6 Protein