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Developmental gene clusters are paradigms for the study of gene regulation; however, the mechanisms that mediate phenomena such as coregulation and enhancer sharing remain largely elusive. Here we address this issue by analysing the vertebrate Irx clusters. We first present a deep enhancer screen of a 2-Mbp span covering the IrxA cluster. Using chromosome conformation capture, we show that enhancer sharing is widespread within the cluster, explaining its evolutionarily conserved organization. We also identify a three-dimensional architecture, probably formed through interactions with CCCTC-binding factor, which is present within both Irx clusters of mouse, Xenopus and zebrafish. This architecture brings the promoters of the first two genes together in the same chromatin landscape. We propose that this unique and evolutionarily conserved genomic architecture of the vertebrate Irx clusters is essential for the coregulation of the first two genes and simultaneously maintains the third gene in a partially independent regulatory landscape.
Figure 1 | Multiple enhancers are distributed along the the IrxA cluster. The black vertical line at the left depicts the IrxA cluster, showing coordinates
(kbp) of human chromosome 5. Columns show enhancer activity of different HCNRs in embryos of mouse (stage E11.5), Xenopus (stage 30) and zebrafish
(24 – 36 h.p.f.). Enhancers are named according to the coordinates (in kilobases) of their human HCNR counteparts. Orthologous regions promote
expression in largely equivalent territories. Arrowheads mark tissues by colour as follows: blue, midbrain; red, hindbrain; white, spinal cord; yellow, kidney;
and purple, otic vesicle.
Figure 5 | Disassembly of the IrxA cluster alters the expression patterns
of IrxA genes. Genome architecture and expression patterns of IrxA genes
in ( a ) Xenopus , ( b ) medaka and ( c ) zebrafish. Expression patterns at
neurula stages are shown in lateral and dorsal (insets) views. In a , b ,
numbers in parentheses indicate the intergenic distances, and in c it
represents the size of orthologous IrxAa DNA associated with each gene.
Red arrowheads point at Irx4 expression in the heart. Coloured rectangles:
enhancers analysed in this study by 3C. Some of these enhancers, as well
as others, were lost upon disaggregation of zebrafish IrxAa cluster. Scale
bars, 0.5 mm.
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