Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

• DOI: 10.1073/pnas.1617141113
• Publication Date: 2016-11-16T13:17:27Z
• Authors: Ruben Schep; Anamaria Necsulea; Eddie Rodríguez-C...; Isabel Guerreiro; Guillaume Andrey; Thi Hanh Nguyen H...; Virginie Marcet; Jozsef Zákány; Denis Duboule; Leonardo Beccari
• Keywords: 0301 basic medicine; mammary gland; mammalian development; Enhancer Elements; Transcription, Genetic; [SDV]Life Sciences [q-bio]; Mice, Transgenic; Inbred C57BL; Transgenic; Mice; 03 medical and health sciences; Mammary Glands, Animal; ddc:590; Genetic; Homeobox; Animals; Developmental; Homeodomain Proteins/genetics/metabolism; Animal/embryology/growth & development/metabolism; Homeodomain Proteins; Sequence Analysis, RNA; info:eu-repo/classification/ddc/590; Inbred CBA; Genes, Homeobox; Gene Expression Regulation, Developmental; TAD; Mammary Glands; [SDV] Life Sciences [q-bio]; Mice, Inbred C57BL; Enhancer Elements, Genetic; Gene Expression Regulation; Genes; Mice, Inbred CBA; RNA; enhancers; Sequence Analysis; Transcription

Significance

During vertebrate evolution, Hox gene function was coopted through the emergence of global enhancers outside the Hox gene clusters. Here, we analyze the regulatory modalities underlying Hoxd gene transcription into the developing mammary glands where Hox proteins are necessary. We report the existence of a long-distance acting mammary bud enhancer located near sequences involved in controlling Hox genes in the limbs. We argue that the particular constitutive chromatin structure found at this locus facilitated the emergence of this enhancer element in mammals by hijacking a regulatory context at work in other cell types, supporting a model wherein enhancer sequences tend to cluster into large regulatory landscapes due to an increased probability to evolve within a preexisting regulatory structure.