Genome-wide occupancy links Hoxa2 to Wnt-β-catenin signaling in mouse embryonic development.
The regulation of gene expression is central to developmental programs and largely depends on the binding of sequence-specific transcription factors with cis-regulatory elements in the genome. Hox transcription factors specify the spatial coordinates of the body axis in all animals with bilateral symmetry, but a detailed knowledge of their molecular function in instructing cell fates is lacking. Here, we used chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) to identify Hoxa2 genomic locations in a time and space when it is actively instructing embryonic development in mouse. Our data reveals that Hoxa2 has large genome coverage and potentially regulates thousands of genes. Sequence analysis of Hoxa2-bound regions identifies high occurrence of two main classes of motifs, corresponding to Hox and Pbx-Hox recognition sequences. Examination of the binding targets of Hoxa2 faithfully captures the processes regulated by Hoxa2 during embryonic development; in addition, it uncovers a large cluster of potential targets involved in the Wnt-signaling pathway. In vivo examination of canonical Wnt-β-catenin signaling reveals activity specifically in Hoxa2 domain of expression, and this is undetectable in Hoxa2 mutant embryos. The comprehensive mapping of Hoxa2-binding sites provides a framework to study Hox regulatory networks in vertebrate developmental processes.
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
Ian J
IJ
Donaldson
Shilu
S
Amin
James J
JJ
Hensman
Eva
E
Kutejova
Magnus
M
Rattray
Neil
N
Lawrence
Andrew
A
Hayes
Christopher M
CM
Ward
Nicoletta
N
Bobola
D000818:Animals; D001665:Binding Sites; D001934:Branchial Region / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D047108:Embryonic Development / Q000235:genetics*; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017422:Sequence Analysis, DNA; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
D018398:Homeodomain Proteins; C489833:Hoxa2 protein, mouse; D051176:beta Catenin