Abstract
Developmental genes in metazoan genomes are surrounded by dense clusters of conserved noncoding elements (CNEs). CNEs exhibit unexplained extreme levels of sequence conservation, with many acting as developmental long-range enhancers. Clusters of CNEs define the span of regulatory inputs for many important developmental regulators and have been described previously as genomic regulatory blocks (GRBs). Their function and distribution around important regulatory genes raises the question of how they relate to 3D conformation of these loci. Here, we show that clusters of CNEs strongly coincide with topological organisation, predicting the boundaries of hundreds of topologically associating domains (TADs) in human and Drosophila. The set of TADs that are associated with high levels of noncoding conservation exhibit distinct properties compared to TADs devoid of extreme noncoding conservation. The close correspondence between extreme noncoding conservation and TADs suggests that these TADs are ancient, revealing a regulatory architecture conserved over hundreds of millions of years.
Highlights
Developmental genes in metazoan genomes are surrounded by dense clusters of conserved noncoding elements (CNEs)
The locations of putative genomic regulatory blocks (GRBs) and their approximate spans can be visualised by plotting the density of CNEs in a sliding window (Fig. 1a); this visualisation is available for multiple genomes in the Ancora browser[33]
We developed a CNE clustering approach that robustly estimates the extent of GRBs, based solely on the distribution of syntenic CNEs in the genome
Summary
Developmental genes in metazoan genomes are surrounded by dense clusters of conserved noncoding elements (CNEs). In Metazoa, many genes involved in developmental regulation are surrounded by syntenic arrays of conserved noncoding elements (CNEs)[1,2,3] These CNEs exhibit extreme levels of conservation over many base pairs, and in some cases more than the equivalent conservation of protein-coding regions[4]. We should emphasise that in regulatory genomics conservation of synteny corresponds to the conservation of collinear arrangement of genes and other conserved sequences between the genomes of two species This syntenic organisation of clusters of CNEs around key developmental genes, called genomic regulatory blocks (GRBs)[3, 13], supports the idea that they are ensembles of regulatory elements that are involved in regulating these genes (Supplementary Fig. 1a). Regulatory elements and genes preferentially interact within the same TAD, suggesting that the boundaries of TADs may act to restrict the influence of enhancers[21, 22]
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