Program in Systems Biology; Department of Biochemistry and Molecular Pharmacology
Cell Biology | Computational Biology | Developmental Biology | Genomics | Systems Biology
The mammalian HoxD cluster lies between two topologically associating domains (TADs) matching distinct enhancer-rich regulatory landscapes. During limb development, the telomeric TAD controls the early transcription of Hoxd genes in forearm cells, whereas the centromeric TAD subsequently regulates more posterior Hoxd genes in digit cells. Therefore, the TAD boundary prevents the terminal Hoxd13 gene from responding to forearm enhancers, thereby allowing proper limb patterning. To assess the nature and function of this CTCF-rich DNA region in embryos, we compared chromatin interaction profiles between proximal and distal limb bud cells isolated from mutant stocks where various parts of this boundary region were removed. The resulting progressive release in boundary effect triggered inter-TAD contacts, favored by the activity of the newly accessed enhancers. However, the boundary was highly resilient, and only a 400-kb deletion, including the whole-gene cluster, was eventually able to merge the neighboring TADs into a single structure. In this unified TAD, both proximal and distal limb enhancers nevertheless continued to work independently over a targeted transgenic reporter construct. We propose that the whole HoxD cluster is a dynamic TAD border and that the exact boundary position varies depending on both the transcriptional status and the developmental context. Press.
CTCF, Hi-C, Hox, TAD, genome architecture, limb
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© 2017 Rodríguez-Carballo et al.; Published by Cold Spring Harbor Laboratory Press. Freely available online through the Genes and Development Open Access option. This article, published in Genes and Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Genes Dev. 2017 Nov 15;31(22):2264-2281. doi: 10.1101/gad.307769.117. Epub 2017 Dec 22. Link to article on publisher's site
Genes and development
Rodriguez-Carballo E, Lopez-Delisle L, Zhan Y, Fabre PJ, Beccari L, El-Idrissi I, Nguyen Huynh TH, Ozadam H, Dekker J, Duboule D. (2017). The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes. Program in Systems Biology Publications. https://doi.org/10.1101/gad.307769.117. Retrieved from https://escholarship.umassmed.edu/sysbio_pubs/123
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.