title: Cdx is crucial for the timing mechanism driving colinear Hox activation and defines a trunk segment in the Hox cluster topology.
abstract: Cdx and Hox transcription factors are important regulators of axial patterning and are required for tissue generation along the vertebrate body axis. Cdx genes have been demonstrated to act upstream of Hox genes in midgestation embryos. Here, we investigate the role of Cdx transcription factors in the gradual colinear activation of the Hox clusters. We found that Hox temporally colinear expression is severely affected in epiblast stem cells derived from Cdx null embryos. We demonstrate that after initiation of 3' Hox gene transcription, Cdx activity is crucial for H3K27ac deposition and for accessibility of cis-regulatory elements around the central - or 'trunk' - Hox genes. We thereby identify a Cdx-responsive segment of HoxA, immediately 5' to the recently defined regulatory domain orchestrating initial transcription of the first Hox gene. We propose that this partition of HoxA into a Wnt-driven 3' part and the newly found Cdx-dependent middle segment of the cluster, forms a structural fundament of Hox colinearity of expression. Subsequently to initial Wnt-induced activation of 3' Hox genes, Cdx transcription factors would act as crucial effectors for activating central Hox genes, until the last gene of the cluster arrests the process.
authors.affiliation: Hubrecht Institute, Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584 CT Utrecht, and UMC Utrecht, the Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Neijts
authors.affiliation: Hubrecht Institute, Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584 CT Utrecht, and UMC Utrecht, the Netherlands.
authors.forename: Shilu
authors.initials: S
authors.lastname: Amin
authors.affiliation: Hubrecht Institute, Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584 CT Utrecht, and UMC Utrecht, the Netherlands.
authors.forename: Carina
authors.initials: C
authors.lastname: van Rooijen
authors.affiliation: Hubrecht Institute, Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584 CT Utrecht, and UMC Utrecht, the Netherlands. Electronic address: j.deschamps@hubrecht.eu.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Deschamps
mesh_terms: D000107:Acetylation; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D000071616:CDX2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005801:Genes, Homeobox / Q000235:genetics; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D006657:Histones; D018398:Homeodomain Proteins; C088144:HoxA protein
keywords: Cdx; Chromatin organization; DNA accessibility; Hox gene regulation; Trunk development; cis-regulatory elements