| 1. |
- Cecchini, Katharine, et al.
(författare)
-
The transcription factor TCFL5 responds to A-MYB to elaborate the male meiotic program in mice
- 2023
-
Ingår i: Reproduction. - 1470-1626 .- 1476-3990. ; 165:2, s. 183-196
-
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.
|
|
| 2. |
- Mou, Haiwei, et al.
(författare)
-
CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer
- 2023
-
Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 259:4, s. 415-427
-
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.
|
|
| 3. |
- Säflund, Martin, et al.
(författare)
-
The MYBL1/TCFL5 transcription network : two collaborative factors with central role in male meiosis
- 2023
-
Ingår i: Biochemical Society Transactions. - 0300-5127 .- 1470-8752. ; 51:6, s. 2163-2172
-
Forskningsöversikt (refereegranskat)abstract
- Male gametogenesis, spermatogenesis, is a stepwise developmental process to generate mature sperm. The most intricate process of spermatogenesis is meiosis during which two successive cell divisions ensue with dramatic cellular and molecular changes to produce haploid cells. After entry into meiosis, several forms of regulatory events control the orderly progression of meiosis and the timely entry into post-meiotic sperm differentiation. Among other mechanisms, changes to gene expression are controlled by key transcription factors. In this review, we will discuss the gene regulatory mechanisms underlying meiotic entry, meiotic progression, and post-meiotic differentiation with a particular emphasis on the MYBL1/TCFL5 regulatory architecture and how this architecture involves in various forms of transcription network motifs to regulate gene expression.
|
|
