Multiple Enhancers Regulate Hoxd Genes and the Hotdog LncRNA during Cecum Budding

• Cecum budding is controlled by at least eight cooperating enhancers
• The regulatory landscape contains two novel lncRNAs (Hotdog and Twin of Hotdog)
• The shared start site of both lncRNAs forms the major 3D contact with Hox genes
• Cecum and limb buds share a common budding toolkit

SummaryHox genes are required for the development of the intestinal cecum, a major organ of plant-eating species. We have analyzed the transcriptional regulation of Hoxd genes in cecal buds and show that they are controlled by a series of enhancers located in a gene desert flanking the HoxD cluster. The start site of two opposite long noncoding RNAs (lncRNAs), Hotdog and Twin of Hotdog, selectively contacts the expressed Hoxd genes in the framework of a topological domain, coinciding with robust transcription of these genes during cecum budding. Both lncRNAs are specifically transcribed in the cecum, albeit bearing no detectable function in trans. Hedgehogs have kept this regulatory potential despite the absence of the cecum, suggesting that these mechanisms are used in other developmental situations. In this context, we discuss the implementation of a common “budding toolkit” between the cecum and the limbs.

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