| 1. |
- Cecchini, Katharine, et al.
(författare)
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The transcription factor TCFL5 responds to A-MYB to elaborate the male meiotic program in mice
- 2023
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Ingår i: Reproduction. - 1470-1626 .- 1476-3990. ; 165:2, s. 183-196
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Tidskriftsartikel (refereegranskat)abstract
- In male mice, the transcription factors STRA8 and MEISON initiate meiosis I. We report that STRA8/MEISON activates the transcription factors A-MYB and TCFL5, which together reprogram gene expression after spermatogonia enter into meiosis. TCFL5 promotes the transcription of genes required for meiosis, mRNA turnover, miR-34/449 production, meiotic exit, and spermiogenesis. This transcriptional architecture is conserved in rhesus macaque, suggesting TCFL5 plays a central role in meiosis and spermiogenesis in placental mammals. Tcfl5(em1/em1) mutants are sterile, and spermatogenesis arrests at the mid- or late-pachytene stage of meiosis. Moreover, Tcfl5(+/em1) mutants produce fewer motile sperm.
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| 2. |
- Mou, Haiwei, et al.
(författare)
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CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer
- 2023
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 259:4, s. 415-427
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Tidskriftsartikel (refereegranskat)abstract
- CRISPR/Cas9-driven cancer modeling studies are based on the disruption of tumor suppressor genes by small insertions or deletions (indels) that lead to frame-shift mutations. In addition, CRISPR/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss-of-function studies. However, how CRISPR/Cas9 influences gain-of-function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of Ctnnb1 (encoding β-catenin) results in exon skipping and generates gain-of-function isoforms in vivo. CRISPR/Cas9-mediated exon skipping of Ctnnb1 induces liver tumor formation in synergy with YAPS127A in mice. We define two distinct exon skipping-induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon-skipped β-catenin transcript isoforms together with YAPS127A phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar CTNNB1 exon-skipping events in patients with hepatocellular carcinoma. Collectively, our findings advance our understanding of β-catenin-related tumorigenesis and reveal that CRISPR/Cas9 can be repurposed, in vivo, to study gain-of-function mutations of oncogenes in cancer.
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