A Regulatory Archipelago Controls Hox Genes Transcription in Digits

• Published in: Cell 2011-11, Vol.147 (5), p.1132-1145
• Main Authors: Montavon, Thomas, Soshnikova, Natalia, Mascrez, Bénédicte, Joye, Elisabeth, Thevenet, Laurie, Splinter, Erik, de Laat, Wouter, Spitz, François, Duboule, Denis
• Format: Article
• Language: English
• Subjects: Animals; Brain - embryology; Brain - metabolism; Deserts; Enhancer Elements, Genetic; Evolution; Extremities - embryology; Extremities - physiology; Gene deletion; Gene Expression Regulation, Developmental; Genes, Homeobox; Homeodomain Proteins; homeotic genes; HOX gene; Humans; Limbs; Mice; Mice, Transgenic; multigene family; Promoter Regions, Genetic; Regulatory sequences; Regulatory Sequences, Nucleic Acid; Transcription; transcription (genetics); Transcription, Genetic; Xenopus
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.10.023

The evolution of digits was an essential step in the success of tetrapods. Among the key players, Hoxd genes are coordinately regulated in developing digits, where they help organize growth and patterns. We identified the distal regulatory sites associated with these genes by probing the three-dimensional architecture of this regulatory unit in developing limbs. This approach, combined with in vivo deletions of distinct regulatory regions, revealed that the active part of the gene cluster contacts several enhancer-like sequences. These elements are dispersed throughout the nearby gene desert, and each contributes either quantitatively or qualitatively to Hox gene transcription in presumptive digits. We propose that this genetic system, which we call a “regulatory archipelago,” provides an inherent flexibility that may partly underlie the diversity in number and morphology of digits across tetrapods, as well as their resilience to drastic variations. [Display omitted] [Display omitted] ► Hox genes active in digits integrate the input of multiple regulatory elements ► The global regulatory architecture of the HoxD locus involves flanking gene deserts ► Alterations in this regulatory structure may fine tune digital morphology in tetrapods Multiple distal enhancer units are spatially coordinated to ensure Hox gene expression and proper development of digits. This regulatory arrangement suggests why digit patterning might be highly diverse between tetrapods yet robust within individuals.