Chromatin topology and the timing of enhancer function at the HoxD locus release_nryil6rlqfbcdohhy7j4lyevvq

by Edgardo Rodriguez-Carballo, Lucille Lopez-Delisle, Andréa Willemin, leonardo Beccari, Sandra Gitto, Bénédicte Mascrez, denis duboule

Published in Proceedings of the National Academy of Sciences of the United States of America by Proceedings of the National Academy of Sciences.

2020   Volume 117, Issue 49, p202015083

Abstract

The <jats:italic>HoxD</jats:italic> gene cluster is critical for proper limb formation in tetrapods. In the emerging limb buds, different subgroups of <jats:italic>Hoxd</jats:italic> genes respond first to a proximal regulatory signal, then to a distal signal that organizes digits. These two regulations are exclusive from one another and emanate from two distinct topologically associating domains (TADs) flanking <jats:italic>HoxD</jats:italic>, both containing a range of appropriate enhancer sequences. The telomeric TAD (T-DOM) contains several enhancers active in presumptive forearm cells and is divided into two sub-TADs separated by a CTCF-rich boundary, which defines two regulatory submodules. To understand the importance of this particular regulatory topology to control <jats:italic>Hoxd</jats:italic> gene transcription in time and space, we either deleted or inverted this sub-TAD boundary, eliminated the CTCF binding sites, or inverted the entire T-DOM to exchange the respective positions of the two sub-TADs. The effects of such perturbations on the transcriptional regulation of <jats:italic>Hoxd</jats:italic> genes illustrate the requirement of this regulatory topology for the precise timing of gene activation. However, the spatial distribution of transcripts was eventually resumed, showing that the presence of enhancer sequences, rather than either their exact topology or a particular chromatin architecture, is the key factor. We also show that the affinity of enhancers to find their natural target genes can overcome the presence of both a strong TAD border and an unfavorable orientation of CTCF sites.
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