RT Journal Article
SR Electronic
T1 THE HOXD CLUSTER IS A DYNAMIC AND RESILIENT TAD BOUNDARY CONTROLLING THE SEGREGATION OF ANTAGONISTIC REGULATORY LANDSCAPES
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 193706
DO 10.1101/193706
A1 Rodríguez-Carballo, Eddie
A1 Lopez-Delisle, Lucille
A1 Zhan, Ye
A1 Fabre, Pierre J.
A1 Beccari, Leonardo
A1 El-Idrissi, Imane
A1 Nguyen Huynh, Thi Hahn
A1 Ozadam, Hakan
A1 Dekker, Job
A1 Duboule, Denis
YR 2017
UL http://biorxiv.org/content/early/2017/11/24/193706.abstract
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.