Dev Cell 2014

HAND2 Targets Define a Network of Transcriptional Regulators that Compartmentalize the Early Limb Bud Mesenchyme


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.
3XFLAG tag inserted into the endogenous HAND2 protein by dRMCE. ChIP-Seq identifies the genomic regions enriched in endogenous HAND2 chromatin complexes from mouse embryos and 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.

The HAND2 target TBX3 is required downstream of HAND2 to refine the posterior expression boundary of Gli3, which is itself a direct HAND2 target.

Osterwalder M., Speziale D., Shoukry M., Mohan R., Ivanek R., Kohler M., Beisel C., Wen X., Scales S.J., Christoffels V.M., Visel A., Lopez-Rios J., and Zeller R.

Paper Details

Year Published:

2014

Journal:

Dev Cell

Paper URL:

Direct Link

Lead Author:

Rolf Zeller