Abassah-Oppong, Samuel , Zoia, Matteo , Mannion, Brandon J , Rouco, Raquel , Tissières, Virginie , Spurrell, Cailyn H , Roland, Virginia , Darbellay, Fabrice , Itum, Anja , Gamart, Julie , Festa-Daroux, Tabitha A , Sullivan, Carly S , Kosicki, Michael , Rodríguez-Carballo, Eddie , Fukuda-Yuzawa, Yoko , Hunter, Riana D , Novak, Catherine S , Plajzer-Frick, Ingrid , Tran, Stella , Akiyama, Jennifer A , Dickel, Diane E , LÓPEZ-RÍOS MORENO, JAVIER, Barozzi, Iros , Andrey, Guillaume , Visel, Axel , Pennacchio, Len A , Cobb, John , Osterwalder, Marco
No
Nat. Commun.
Article
Científica
10/10/2024
001336988700005
2-s2.0-85206025432
Approximately a quarter of the human genome consists of gene deserts, large regions devoid of genes often located adjacent to developmental genes and thought to contribute to their regulation. However, defining the regulatory functions embedded within these deserts is challenging due to their large size. Here, we explore the cis-regulatory architecture of a gene desert flanking the Shox2 gene, which encodes a transcription factor indispensable for proximal limb, craniofacial, and cardiac pacemaker development. We identify the gene desert as a regulatory hub containing more than 15 distinct enhancers recapitulating anatomical subdomains of Shox2 expression. Ablation of the gene desert leads to embryonic lethality due to Shox2 depletion in the cardiac sinus venosus, caused in part by the loss of a specific distal enhancer. The gene desert is also required for stylopod morphogenesis, mediated via distributed proximal limb enhancers. In summary, our study establishes a multi-layered role of the Shox2 gene desert in orchestrating pleiotropic developmental expression through modular arrangement and coordinated dynamics of tissue-specific enhancers.
Animals; Enhancer Elements, Genetic; Gene Expression Regulation, Developmental; Homeodomain Proteins; Humans; Mice; Morphogenesis; cis acting element; homeodomain protein; SHOX2 protein, human; Shox2 protein, mouse; ablation; anatomy; embryonic development; gene expression; genome; limb; pleiotropy; adult; animal cell; animal experiment; animal tissue; Article; chromatin structure; controlled study; craniofacial development; DNA flanking region; embryo; embryo death; embryo development; enhancer region; female; fetus; gene; gene dosage; gene editing; gene expression; gene regulatory network; heart development; human; human tissue; limb development; male; morphogenesis; mouse; newborn; nonhuman; pleiotropy; promoter region; protein depletion; shox2 gene; sinus node; sinus venosus; tissue specificity; animal; enhancer region; gene expression regulation; genetics; metabolism