Format

Send to

Choose Destination
BMC Biol. 2019 Jul 12;17(1):55. doi: 10.1186/s12915-019-0677-x.

Impact of genome architecture on the functional activation and repression of Hox regulatory landscapes.

Author information

1
Laboratory of Developmental Genomics, Department of Genetics and Evolution, University of Geneva, 1211, Geneva 4, Switzerland.
2
School of Life Sciences, Federal Institute of Technology, Lausanne, 1015, Lausanne, Switzerland.
3
Present Address: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohoma, Kanagawa, 230-0045, Japan.
4
Laboratory of Artificial and Natural Evolution, Department of Genetics and Evolution, University of Geneva, 1211, Geneva 4, Switzerland.
5
Laboratory of Developmental Genomics, Department of Genetics and Evolution, University of Geneva, 1211, Geneva 4, Switzerland. Denis.Duboule@unige.ch.
6
School of Life Sciences, Federal Institute of Technology, Lausanne, 1015, Lausanne, Switzerland. Denis.Duboule@unige.ch.
7
Collège de France, 75005, Paris, France. Denis.Duboule@unige.ch.

Abstract

BACKGROUND:

The spatial organization of the mammalian genome relies upon the formation of chromatin domains of various scales. At the level of gene regulation in cis, collections of enhancer sequences define large regulatory landscapes that usually match with the presence of topologically associating domains (TADs). These domains often contain ranges of enhancers displaying similar or related tissue specificity, suggesting that in some cases, such domains may act as coherent regulatory units, with a global on or off state. By using the HoxD gene cluster, which specifies the topology of the developing limbs via highly orchestrated regulation of gene expression, as a paradigm, we investigated how the arrangement of regulatory domains determines their activity and function.

RESULTS:

Proximal and distal cells in the developing limb express different levels of Hoxd genes, regulated by flanking 3' and 5' TADs, respectively. We characterized the effect of large genomic rearrangements affecting these two TADs, including their fusion into a single chromatin domain. We show that, within a single hybrid TAD, the activation of both proximal and distal limb enhancers globally occurred as when both TADs are intact. However, the activity of the 3' TAD in distal cells is generally increased in the fused TAD, when compared to wild type where it is silenced. Also, target gene activity in distal cells depends on whether or not these genes had previously responded to proximal enhancers, which determines the presence or absence of H3K27me3 marks. We also show that the polycomb repressive complex 2 is mainly recruited at the Hox gene cluster and can extend its coverage to far-cis regulatory sequences as long as confined to the neighboring TAD structure.

CONCLUSIONS:

We conclude that antagonistic limb proximal and distal enhancers can exert their specific effects when positioned into the same TAD and in the absence of their genuine target genes. We also conclude that removing these target genes reduced the coverage of a regulatory landscape by chromatin marks associated with silencing, which correlates with its prolonged activity in time.

KEYWORDS:

Enhancers; Genome architecture; Polycomb; Regulatory landscapes; TAD; Tetrapod evolution

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center