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

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.; Lopez-Rios, Javier; Barozzi, Iros; Andrey, Guillaume; Visel, Axel; Pennacchio, Len A.; Cobb, John; Osterwalder, Marco

doi:10.1038/s41467-024-53009-7

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

Journal Article · 10 October 2024 · Nature Communications

DOI: https://doi.org/10.1038/s41467-024-53009-7 · OSTI ID:2479280

^[1]; Zoia, Matteo ^[2]; Mannion, Brandon J. ^[3];

^[4]; Tissières, Virginie ^[5];

^[6]; Roland, Virginia ^[2];

^[7]; Itum, Anja ^[8]; Gamart, Julie ^[2]; Festa-Daroux, Tabitha A. ^[8]; Sullivan, Carly S. ^[8]; Kosicki, Michael ^[6]; Rodríguez-Carballo, Eddie ^[4]; Fukuda-Yuzawa, Yoko ^[6]; Hunter, Riana D. ^[6]; Novak, Catherine S. ^[6]; Plajzer-Frick, Ingrid ^[6]; Tran, Stella ^[6];

^[6] more »

Fort Hays State University, Hays, KS (United States); University of Calgary, AB (Canada)
University of Bern (Switzerland)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); University of California, Berkeley, CA (United States)
University of Geneva (Switzerland)
University of Bern (Switzerland); CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Seville (Spain)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); University of Geneva (Switzerland)
University of Calgary, AB (Canada)
CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Seville (Spain); Universidad Loyola Andalucía, Seville (Spain)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Medical University of Vienna (Austria)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); University of California, Merced, CA (United States)
University of Bern (Switzerland); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: MICINN; National Institutes of Health (NIH); Natural Sciences and Engineering Research Council of Canada; Novartis Foundation for Medical-Biological Research; Swiss Heart Foundation; Swiss National Science Foundation (SNSF); USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science (BSS)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2479280

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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