PT  - JOURNAL ARTICLE
AU  - Rodríguez-Carballo, Eddie
AU  - Lopez-Delisle, Lucille
AU  - Zhan, Ye
AU  - Fabre, Pierre J.
AU  - Beccari, Leonardo
AU  - El-Idrissi, Imane
AU  - Nguyen Huynh, Thi Hahn
AU  - Ozadam, Hakan
AU  - Dekker, Job
AU  - Duboule, Denis
TI  - THE HOXD CLUSTER IS A DYNAMIC AND RESILIENT TAD BOUNDARY CONTROLLING THE SEGREGATION OF ANTAGONISTIC REGULATORY LANDSCAPES
AID  - 10.1101/193706
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 193706
4099  - http://biorxiv.org/content/early/2017/11/24/193706.short
4100  - http://biorxiv.org/content/early/2017/11/24/193706.full
AB  - 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 gene 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 to respond to forearm enhancers, thereby allowing proper limb patterning. To assess the nature and function of this CTCF-rich DNA region in embryo, we compared chromatin interaction profiles between proximal and distal limb bud cells isolated from mutant stocks where various parts or 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 400kb large 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.