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

Autor: Wu XS; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.; Genetics Program, Stony Brook University, Stony Brook, NY, USA., He XY; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Ipsaro JJ; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.; Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Huang YH; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Preall JB; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Ng D; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Shue YT; Department of Pediatrics, Stanford University, Stanford, CA, USA.; Department of Genetics, Stanford University, Stanford, CA, USA., Sage J; Department of Pediatrics, Stanford University, Stanford, CA, USA.; Department of Genetics, Stanford University, Stanford, CA, USA., Egeblad M; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Joshua-Tor L; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.; Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Vakoc CR; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. vakoc@cshl.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Jul; Vol. 607 (7917), pp. 169-175. Date of Electronic Publication: 2022 May 16.
DOI: 10.1038/s41586-022-04842-7
Abstrakt: Tuft cells are a rare chemosensory lineage that coordinates immune and neural responses to foreign pathogens in mucosal tissues 1 . Recent studies have also revealed tuft-cell-like human tumours 2,3 , 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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