Etv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud

Naoko Koyano-Nakagawa, Wuming Gong, Satyabrata Das, Joshua W. M. Theisen, Tran B. Swanholm, Daniel Ly, Nikita Dsouza, Bhairab N. Singh, Hiroko Kawakami, Samantha Young, Katherine Q. Chen, Yasuhiko Kawakami () and Daniel J. Garry ()
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Naoko Koyano-Nakagawa: University of Minnesota
Wuming Gong: University of Minnesota
Satyabrata Das: University of Minnesota
Joshua W. M. Theisen: University of Minnesota
Tran B. Swanholm: University of Minnesota
Daniel Ly: University of Minnesota
Nikita Dsouza: University of Minnesota
Bhairab N. Singh: University of Minnesota
Hiroko Kawakami: University of Minnesota
Samantha Young: University of Minnesota
Katherine Q. Chen: University of Minnesota
Yasuhiko Kawakami: University of Minnesota
Daniel J. Garry: University of Minnesota

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31848-6

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