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The splicing factor Sf3b1 regulates erythroid maturation and proliferation via TGF? signaling in zebrafish.

ABSTRACT: The spliceosomal component Splicing Factor 3B, subunit 1 (SF3B1) is one of the most prevalently mutated factors in the bone marrow failure disorder myelodysplastic syndrome. There is a strong clinical correlation between SF3B1 mutations and erythroid defects, such as refractory anemia with ringed sideroblasts, but the role of SF3B1 in normal erythroid development is largely unknown. Loss-of-function zebrafish mutants for sf3b1 develop a macrocytic anemia. Here, we explore the underlying mechanism for anemia associated with sf3b1 deficiency in vivo. We found that sf3b1 mutant erythroid progenitors display a G0/G1 cell-cycle arrest with mutant erythrocytes showing signs of immaturity. RNA-sequencing analysis of sf3b1 mutant erythroid progenitors revealed normal expression of red blood cell regulators such as gata1, globin genes, and heme biosynthetic factors, but upregulation of genes in the transforming growth factor ? (TGF?) pathway. As TGF? signaling is a known inducer of quiescence, the data suggest that activation of the pathway could trigger sf3b1 deficiency-induced anemia via cell-cycle arrest. Indeed, we found that inhibition of TGF? signaling released the G0/G1 block in erythroid progenitors. Surprisingly, removal of this checkpoint enhanced rather than suppressed the anemia, indicating that the TGF?-mediated cell-cycle arrest is protective for sf3b1-mutant erythrocytes. Together, these data suggest that macrocytic anemia arising from Sf3b1 deficiency is likely due to pleiotropic and distinct effects on cell-cycle progression and maturation.

SUBMITTER: De La Garza A

PROVIDER: S-EPMC6650725 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The splicing factor Sf3b1 regulates erythroid maturation and proliferation via TGFβ signaling in zebrafish.

De La Garza Adriana A Cameron Rosannah C RC Gupta Varun V Fraint Ellen E Nik Sara S Bowman Teresa V TV

Blood advances 20190701 14

The spliceosomal component Splicing Factor 3B, subunit 1 (SF3B1) is one of the most prevalently mutated factors in the bone marrow failure disorder myelodysplastic syndrome. There is a strong clinical correlation between SF3B1 mutations and erythroid defects, such as refractory anemia with ringed sideroblasts, but the role of SF3B1 in normal erythroid development is largely unknown. Loss-of-function zebrafish mutants for <i>sf3b1</i> develop a macrocytic anemia. Here, we explore the underlying m ...[more]

PMID: 31300417

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Project description:Although endometrial cancer is the most common cancer of the female reproductive tract, we have little understanding of what controls endometrial cancer beyond the transcriptional effects of steroid hormones such as estrogen. As a result, we have limited therapeutic options for the ~62,000 women diagnosed with endometrial cancer each year in the United States. Here, in an attempt to identify new prognostic and therapeutic targets, we focused on a new area for this cancer-alternative mRNA splicing-and investigated whether splicing factor, SF3B1, plays an important role in endometrial cancer pathogenesis. Using a tissue microarray, we found that human endometrial tumors expressed more SF3B1 protein than non-cancerous tissues. Furthermore, SF3B1 knockdown reduced in vitro proliferation, migration, and invasion of the endometrial cancer cell lines Ishikawa and AN3CA. Similarly, the SF3B1 inhibitor, Pladienolide-B (PLAD-B), reduced the Ishikawa and AN3CA cell proliferation and invasion in vitro. Moreover, PLAD-B reduced tumor growth in an orthotopic endometrial cancer mouse model. Using RNA-Seq approach, we identified ~2000 differentially expressed genes (DEGs) with SF3B1 knockdown in endometrial cancer cells. Additionally, alternative splicing (AS) events analysis revealed that SF3B1 depletion led to alteration in multiple categories of AS events including alternative exon skipping (ES), transcript start site usage (TSS), and transcript termination site (TTS) usage. Subsequently, bioinformatics analysis showed KSR2 as a potential candidate for SF3B1-mediated functions in endometrial cancer. Specifically, loss of SF3B1 led to decrease in KSR2 expression, owing to reduced maturation of KSR2 pre-mRNA to a mature RNA. Importantly, we found rescuing the KSR2 expression with SF3B1 knockdown partially restored the cell growth of endometrial cancer cells. Taken together, our data suggest that SF3B1 plays a crucial oncogenic role in the tumorigenesis of endometrial cancer and hence may support the development of SF3B1 inhibitors to treat this disease.

Dataset Information

The splicing factor Sf3b1 regulates erythroid maturation and proliferation via TGF? signaling in zebrafish.

Publications

The splicing factor Sf3b1 regulates erythroid maturation and proliferation via TGFβ signaling in zebrafish.

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