title: HAND2 targets define a network of transcriptional regulators that compartmentalize the early limb bud mesenchyme.
abstract: The genetic networks that govern vertebrate development are well studied, but how the interactions of trans-acting factors with cis-regulatory modules (CRMs) are integrated into spatiotemporal regulation of gene expression is not clear. The transcriptional regulator HAND2 is required during limb, heart, and branchial arch development. Here, we identify the genomic regions enriched in HAND2 chromatin complexes from mouse embryos and limb buds. Then we analyze the HAND2 target CRMs in the genomic landscapes encoding transcriptional regulators required in early limb buds. HAND2 controls the expression of genes functioning in the proximal limb bud and orchestrates the establishment of anterior and posterior polarity of the nascent limb bud mesenchyme by impacting Gli3 and Tbx3 expression. TBX3 is required downstream of HAND2 to refine the posterior Gli3 expression boundary. Our analysis uncovers the transcriptional circuits that function in establishing distinct mesenchymal compartments downstream of HAND2 and upstream of SHH signaling.
authors.affiliation: Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Osterwalder
authors.affiliation: Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Dario
authors.initials: D
authors.lastname: Speziale
authors.affiliation: Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Malak
authors.initials: M
authors.lastname: Shoukry
authors.affiliation: Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, the Netherlands.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Mohan
authors.affiliation: Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Ivanek
authors.affiliation: Department for Biosystems Science and Engineering, Federal Institute of Technology Zurich, 4058 Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Kohler
authors.affiliation: Department for Biosystems Science and Engineering, Federal Institute of Technology Zurich, 4058 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Beisel
authors.affiliation: Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wen
authors.affiliation: Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Suzie J
authors.initials: SJ
authors.lastname: Scales
authors.affiliation: Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, the Netherlands.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
authors.affiliation: Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; School of Natural Sciences, University of California, Merced, Merced, CA 95343, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Visel
authors.affiliation: Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland. Electronic address: javier.lopez-rios@unibas.ch.
authors.forename: Javier
authors.initials: J
authors.lastname: Lopez-Rios
authors.affiliation: Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland. Electronic address: rolf.zeller@unibas.ch.
authors.forename: Rolf
authors.initials: R
authors.lastname: Zeller
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018878:Limb Buds / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; C498766:Hand2 protein, mouse