Como o genoma estabelece sua microarquitetura funcional: mero acaso, fortuita necessidade ou design inteligente?

quarta-feira, agosto 30, 2017

Large scale genomic reorganization of topological domains at the HoxD locus

Pierre J. Fabre, Marion Leleu, Benjamin H. Mormann, Lucille Lopez-Delisle, Daan Noordermeer, Leonardo Beccari and Denis Duboule

Genome Biology201718:149

Received: 13 March 2017Accepted: 14 July 2017Published: 7 August 2017



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.


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.


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.


Regulatory landscape Chromatin organization Gene regulation Topologically associating domains TAD Enhancer Hox CTCF Limb development

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