OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage

Xiaoli S. Wu, Xue-Yan He, Jonathan J. Ipsaro, Yu-Han Huang, Jonathan B. Preall, David Ng, Yan Ting Shue, Julien Sage, Mikala Egeblad, Leemor Joshua-Tor and Christopher R. Vakoc ()
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Xiaoli S. Wu: Cold Spring Harbor Laboratory
Xue-Yan He: Cold Spring Harbor Laboratory
Jonathan J. Ipsaro: Cold Spring Harbor Laboratory
Yu-Han Huang: Cold Spring Harbor Laboratory
Jonathan B. Preall: Cold Spring Harbor Laboratory
David Ng: Cold Spring Harbor Laboratory
Yan Ting Shue: Stanford University
Julien Sage: Stanford University
Mikala Egeblad: Cold Spring Harbor Laboratory
Leemor Joshua-Tor: Cold Spring Harbor Laboratory
Christopher R. Vakoc: Cold Spring Harbor Laboratory

Nature, 2022, vol. 607, issue 7917, 169-175

Abstract: Abstract Tuft cells are a rare chemosensory lineage that coordinates immune and neural responses to foreign pathogens in mucosal tissues1. Recent studies have also revealed tuft-cell-like human tumours2,3, particularly as a variant of small-cell lung cancer. Both normal and neoplastic tuft cells share a genetic requirement for the transcription factor POU2F3 (refs. 2,4), although the transcriptional mechanisms that generate this cell type are poorly understood. Here we show that binding of POU2F3 to the uncharacterized proteins C11orf53 and COLCA2 (renamed here OCA-T1/POU2AF2 and OCA-T2/POU2AF3, respectively) is critical in the tuft cell lineage. OCA-T1 and OCA-T2 are paralogues of the B-cell-specific coactivator OCA-B; all three proteins are encoded in a gene cluster and contain a conserved peptide that binds to class II POU transcription factors and a DNA octamer motif in a bivalent manner. We demonstrate that binding between POU2F3 and OCA-T1 or OCA-T2 is essential in tuft-cell-like small-cell lung cancer. Moreover, we generated OCA-T1-deficient mice, which are viable but lack tuft cells in several mucosal tissues. These findings reveal that the POU2F3–OCA-T complex is the master regulator of tuft cell identity and a molecular vulnerability of tuft-cell-like small-cell lung cancer.

Date: 2022
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DOI: 10.1038/s41586-022-04842-7

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