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Dev Cell. 2014 Nov 10;31(3):345-357. doi: 10.1016/j.devcel.2014.09.018. Epub 2014 Nov 10.

HAND2 targets define a network of transcriptional regulators that compartmentalize the early limb bud mesenchyme.

Author information

1
Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
2
Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
3
Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, the Netherlands.
4
Department for Biosystems Science and Engineering, Federal Institute of Technology Zurich, 4058 Basel, Switzerland.
5
Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
6
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.
7
Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland. Electronic address: javier.lopez-rios@unibas.ch.
8
Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland. Electronic address: rolf.zeller@unibas.ch.

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.

PMID:
25453830
PMCID:
PMC4357275
DOI:
10.1016/j.devcel.2014.09.018
[Indexed for MEDLINE]
Free PMC Article

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