title: Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape.
abstract: Vertebrate Hox genes encode transcription factors operating during the development of multiple organs and structures. However, the evolutionary mechanism underlying this remarkable pleiotropy remains to be fully understood. Here, we show that Hoxd8 and Hoxd9, two genes of the HoxD complex, are transcribed during mammary bud (MB) development. However, unlike in other developmental contexts, their coexpression does not rely on the same regulatory mechanism. Hoxd8 is regulated by the combined activity of closely located sequences and the most distant telomeric gene desert. On the other hand, Hoxd9 is controlled by an enhancer-rich region that is also located within the telomeric gene desert but has no impact on Hoxd8 transcription, thus constituting an exception to the global regulatory logic systematically observed at this locus. The latter DNA region is also involved in Hoxd gene regulation in other contexts and strongly interacts with Hoxd9 in all tissues analyzed thus far, indicating that its regulatory activity was already operational before the appearance of mammary glands. Within this DNA region and neighboring a strong limb enhancer, we identified a short sequence conserved in therian mammals and capable of enhancer activity in the MBs. We propose that Hoxd gene regulation in embryonic MBs evolved by hijacking a preexisting regulatory landscape that was already at work before the emergence of mammals in structures such as the limbs or the intestinal tract.
authors.affiliation: Department of Genetics and Evolution, University of Geneva,1211 Geneva, Switzerland.
authors.forename: Ruben
authors.initials: R
authors.lastname: Schep
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Anamaria
authors.initials: A
authors.lastname: Necsulea
authors.affiliation: Department of Genetics and Evolution, University of Geneva,1211 Geneva, Switzerland.
authors.forename: Eddie
authors.initials: E
authors.lastname: Rodríguez-Carballo
authors.affiliation: Department of Genetics and Evolution, University of Geneva,1211 Geneva, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Guerreiro
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Andrey
authors.affiliation: Department of Genetics and Evolution, University of Geneva,1211 Geneva, Switzerland.
authors.forename: Thi Hanh
authors.initials: TH
authors.lastname: Nguyen Huynh
authors.affiliation: Department of Genetics and Evolution, University of Geneva,1211 Geneva, Switzerland.
authors.forename: Virginie
authors.initials: V
authors.lastname: Marcet
authors.affiliation: Department of Genetics and Evolution, University of Geneva,1211 Geneva, Switzerland.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Zákány
authors.affiliation: Department of Genetics and Evolution, University of Geneva,1211 Geneva, Switzerland; denis.duboule@unige.ch.|School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Duboule
authors.affiliation: Department of Genetics and Evolution, University of Geneva,1211 Geneva, Switzerland.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Beccari
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic
chemical_list: D018398:Homeodomain Proteins
keywords: TAD; enhancers; mammalian development; mammary gland