A gene desert required for regulatory control of pleiotropic Shox2 expression and embryonic survival

Samuel Abassah-Oppong, Matteo Zoia, Brandon J. Mannion, Raquel Rouco, Virginie Tissières, Cailyn H. Spurrell, Virginia Roland, Fabrice Darbellay, Anja Itum, Julie Gamart, Tabitha A. Festa-Daroux, Carly S. Sullivan, Michael Kosicki, Eddie Rodríguez-Carballo, Yoko Fukuda-Yuzawa, Riana D. Hunter, Catherine S. Novak, Ingrid Plajzer-Frick, Stella Tran, Jennifer A. Akiyama, Diane E. Dickel, Javier Lopez-Rios, Iros Barozzi, Guillaume Andrey, Axel Visel, Len A. Pennacchio, John Cobb () and Marco Osterwalder ()
Additional contact information
Samuel Abassah-Oppong: University of Calgary, 2500 University Drive N.W.
Matteo Zoia: University of Bern
Brandon J. Mannion: Lawrence Berkeley National Laboratory
Raquel Rouco: University of Geneva
Virginie Tissières: University of Bern
Cailyn H. Spurrell: Lawrence Berkeley National Laboratory
Virginia Roland: University of Bern
Fabrice Darbellay: Lawrence Berkeley National Laboratory
Anja Itum: University of Calgary, 2500 University Drive N.W.
Julie Gamart: University of Bern
Tabitha A. Festa-Daroux: University of Calgary, 2500 University Drive N.W.
Carly S. Sullivan: University of Calgary, 2500 University Drive N.W.
Michael Kosicki: Lawrence Berkeley National Laboratory
Eddie Rodríguez-Carballo: University of Geneva
Yoko Fukuda-Yuzawa: Lawrence Berkeley National Laboratory
Riana D. Hunter: Lawrence Berkeley National Laboratory
Catherine S. Novak: Lawrence Berkeley National Laboratory
Ingrid Plajzer-Frick: Lawrence Berkeley National Laboratory
Stella Tran: Lawrence Berkeley National Laboratory
Jennifer A. Akiyama: Lawrence Berkeley National Laboratory
Diane E. Dickel: Lawrence Berkeley National Laboratory
Javier Lopez-Rios: CSIC-Universidad Pablo de Olavide-Junta de Andalucía
Iros Barozzi: Lawrence Berkeley National Laboratory
Guillaume Andrey: University of Geneva
Axel Visel: Lawrence Berkeley National Laboratory
Len A. Pennacchio: Lawrence Berkeley National Laboratory
John Cobb: University of Calgary, 2500 University Drive N.W.
Marco Osterwalder: University of Bern

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53009-7

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