Sequential and Directional Insulation by Conserved CTCF Sites Underlies the Hox Timer in Stembryos
Authors
Affiliations
During development, Hox genes are temporally activated according to their relative positions on their clusters, contributing to the proper identities of structures along the rostrocaudal axis. To understand the mechanism underlying this Hox timer, we used mouse embryonic stem cell-derived stembryos. Following Wnt signaling, the process involves transcriptional initiation at the anterior part of the cluster and a concomitant loading of cohesin complexes enriched on the transcribed DNA segments, that is, with an asymmetric distribution favoring the anterior part of the cluster. Chromatin extrusion then occurs with successively more posterior CTCF sites acting as transient insulators, thus generating a progressive time delay in the activation of more posterior-located genes due to long-range contacts with a flanking topologically associating domain. Mutant stembryos support this model and reveal that the presence of evolutionary conserved and regularly spaced intergenic CTCF sites controls the precision and the pace of this temporal mechanism.
Ma F, Ollikainen N, Du H, Braikia F, Cui N, Bianchi A Nat Commun. 2025; 16(1):2148.
PMID: 40032827 PMC: 11876664. DOI: 10.1038/s41467-025-57373-w.
Bridging spatial and temporal scales of developmental gene regulation.
Cardona A, Peixoto M, Borjigin T, Gregor T ArXiv. 2025; .
PMID: 39975433 PMC: 11838700.
Huang Y, Verstegen M, Tjalsma S, Krijger P, Gupta K, Park M Genes Dev. 2025; 39(5-6):348-363.
PMID: 39870429 PMC: 11874980. DOI: 10.1101/gad.352235.124.
Nguyen N, Farge E Nat Commun. 2024; 15(1):10695.
PMID: 39702750 PMC: 11659590. DOI: 10.1038/s41467-024-55100-5.
HOX gene expression in the developing human spine.
Lawrence J, Roberts K, Tuck E, Li T, Mamanova L, Balogh P Nat Commun. 2024; 15(1):10023.
PMID: 39567486 PMC: 11579336. DOI: 10.1038/s41467-024-54187-0.