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

Wu, Xiaoli S, He, Xue-Yan, Ipsaro, Jonathan J, Huang, Yu-Han, Preall, Jonathan B, Ng, David, Shue, Yan Ting, Sage, Julien, Egeblad, Mikala, Joshua-Tor, Leemor, Vakoc, Christopher R (May 2022) OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage. Nature. ISSN 0028-0836

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 tumors2,3, particularly as a variant form of small cell lung cancer (SCLC). Both normal and neoplastic tuft cells share a genetic requirement for the transcription factor POU2F32,4, 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 and OCA-T2, respectively) is critical in the tuft cell lineage. OCA-T1 and OCA-T2 are paralogs of the B cell-specific coactivator OCA-B, which are encoded in a gene cluster and harbor a conserved peptide that binds to class II POU transcription factors and octamer motif DNA in a bivalent manner. We demonstrate that binding between POU2F3 and OCA-T1 or OCA-T2 is essential in tuft cell-like SCLC. In addition, we generated OCA-T1 knockout mice, which are viable but lack tuft cells in several mucosal tissues. These findings reveal the POU2F3-OCA-T complex as the master regulator of tuft cell identity and a prominent molecular vulnerability of tuft cell-like SCLC.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent diseases & disorders > cancer > cancer types > small cell lung cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells > tuft cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells > tuft cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells > tuft cell diseases & disorders > cancer > cancer types
CSHL Authors:	Wu, Xiaoli He, Xueyan Ipsaro, Jonathan J. Huang, Yuhan Preall, Jonathan Ng, David Egeblad, Mikala Joshua-Tor, Leemor Vakoc, Christopher R.
Communities:	CSHL labs > Egeblad lab CSHL labs > Joshua-Tor lab CSHL labs > Preall lab CSHL labs > Vakoc lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	16 May 2022
Date Deposited:	18 May 2022 13:51
Last Modified:	09 Feb 2024 20:54
PMCID:	PMC9419707
URI:	https://repository.cshl.edu/id/eprint/40610

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