期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：E7720-E7729
DOI：10.1073/pnas.1617141113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDuring 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. 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.
关键词：enhancers ; TAD ; mammalian development ; mammary gland
