Large scale genomic reorganization of topological domains at the HoxD locus.

Abstract:

BACKGROUND:The transcriptional activation of HoxD genes during mammalian limb development involves dynamic interactions with two topologically associating domains (TADs) flanking the HoxD cluster. In particular, the activation of the most posterior HoxD genes in developing digits is controlled by regulatory elements located in the centromeric TAD (C-DOM) through long-range contacts. RESULTS:To assess the structure-function relationships underlying such interactions, we measured compaction levels and TAD discreteness using a combination of chromosome conformation capture (4C-seq) and DNA FISH. We assessed the robustness of the TAD architecture by using a series of genomic deletions and inversions that impact the integrity of this chromatin domain and that remodel long-range contacts. We report multi-partite associations between HoxD genes and up to three enhancers. We find that the loss of native chromatin topology leads to the remodeling of TAD structure following distinct parameters. CONCLUSIONS:Our results reveal that the recomposition of TAD architectures after large genomic re-arrangements is dependent on a boundary-selection mechanism in which CTCF mediates the gating of long-range contacts in combination with genomic distance and sequence specificity. Accordingly, the building of a recomposed TAD at this locus depends on distinct functional and constitutive parameters.

journal_name

Genome Biol

journal_title

Genome biology

authors

Fabre PJ,Leleu M,Mormann BH,Lopez-Delisle L,Noordermeer D,Beccari L,Duboule D

doi

10.1186/s13059-017-1278-z

subject

Has Abstract

pub_date

2017-08-07 00:00:00

pages

149

issue

1

eissn

1474-7596

issn

1474-760X

pii

10.1186/s13059-017-1278-z

journal_volume

18

pub_type

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