Sonic hedgehog (Shh) is essential for limb development, and the mechanisms that govern the propagation and maintenance of its expression has been well studied; however, the mechanisms that govern the initiation of Shh expression are incomplete. Here we report that ETV2 initiates Shh expression by changing the chromatin status of the developmental limb enhancer, ZRS. Etv2 expression precedes Shh in limb buds, and Etv2 inactivation prevents the opening of limb chromatin, including the ZRS, resulting in an absence of Shh expression. Etv2 overexpression in limb buds causes nucleosomal displacement at the ZRS, ectopic Shh expression, and polydactyly. Areas of nucleosome displacement coincide with ETS binding site clusters. ETV2 also functions as a transcriptional activator of ZRS and is antagonized by ETV4/5 repressors. Known human polydactyl mutations introduce novel ETV2 binding sites in the ZRS, suggesting that ETV2 dosage regulates ZRS activation. These studies identify ETV2 as a pioneer transcription factor (TF) regulating the onset of Shh expression, having both a chromatin regulatory role and a transcriptional activation role.
|Original language||English (US)|
|State||Published - Dec 2022|
Bibliographical noteFunding Information:
This work was supported by the NIH (1U01HL134764 to DJG, 5U01HL100407 to DJG, and R01AR064195 to YK). We are grateful to Drs. Chi-chung Hui, Juan Carlos Izpisua Belmonte, Michael Roberts, Dennis K. Watson, Vincenzo Zappavigna, Yasushi Nakagawa, and Rolf Zeller for sharing plasmids and equipment. The authors acknowledge Mark Sanders, Sandra Wagner, Debra Kulhanek, Erik Skie, Pruthvi Shah, Lars Meisner, and Akiko Nakagawa for technical assistance. The authors acknowledge the efforts of Cynthia Faraday for figure preparation.
© 2022, The Author(s).
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University Imaging Centers
Mark A Sanders (Program Director) & Guillermo Marques (Scientific Director)University Imaging Centers