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SRSF10 regulates alternative splicing and is required for adipocyte differentiation.

ABSTRACT: During adipocyte differentiation, significant alternative splicing changes occur in association with the adipogenic process. However, little is known about roles played by splicing factors in this process. We observed that mice deficient for the splicing factor SRSF10 exhibit severely impaired development of subcutaneous white adipose tissue as a result of defects in adipogenic differentiation. To identify splicing events responsible for this, RNA-seq analysis was performed using embryonic fibroblast cells. Several SRSF10-affected splicing events that are implicated in adipogenesis have been identified. Skipping of lipin1 exon 7 is controlled by SRSF10-regulated cis-element located in the constitutive exon 8. The activity of this element depends on the binding of SRSF10 and correlates with the relative abundance of lipin1a mRNA. A series of experiments demonstrated that SRSF10 controls the production of lipin1a and thus promotes adipocyte differentiation. Indeed, lipin1a expression could rescue SRSF10-mediated adipogenic defects. Taken together, our results identify SRSF10 as an essential regulator for adipocyte differentiation and also provide new insights into splicing control by SRSF10 in lipin1 pre-mRNA splicing.

ORGANISM(S): Mus musculus

PROVIDER: GSE54226 | GEO | 2014/05/12

SECONDARY ACCESSION(S): PRJNA235967

REPOSITORIES: GEO

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SRSF10 regulates alternative splicing and is required for adipocyte differentiation.

Project description:During adipocyte differentiation, significant alternative splicing changes occur in association with the adipogenic process. However, little is known about roles played by splicing factors in this process. We observed that mice deficient for the splicing factor SRSF10 exhibit severely impaired development of subcutaneous white adipose tissue as a result of defects in adipogenic differentiation. To identify splicing events responsible for this, RNA-seq analysis was performed using embryonic fibroblast cells. Several SRSF10-affected splicing events that are implicated in adipogenesis have been identified. Skipping of lipin1 exon 7 is controlled by SRSF10-regulated cis-element located in the constitutive exon 8. The activity of this element depends on the binding of SRSF10 and correlates with the relative abundance of lipin1a mRNA. A series of experiments demonstrated that SRSF10 controls the production of lipin1a and thus promotes adipocyte differentiation. Indeed, lipin1a expression could rescue SRSF10-mediated adipogenic defects. Taken together, our results identify SRSF10 as an essential regulator for adipocyte differentiation and also provide new insights into splicing control by SRSF10 in lipin1 pre-mRNA splicing. RNA-seq for wide type (WT) and SRSF10-deficient (KO) mouse MEF cells

2014-05-12 | E-GEOD-54226 | biostudies-arrayexpress

Transcriptome analysis of alternative splicing events regulated by SRSF10 reveals position-dependent splicing modulation.

Project description:Splicing factor SRSF10 is known to function as a sequence-specific splicing activator. Here, we used RNA-seq coupled with bioinformatics analysis to identify the extensive splicing network regulated by SRSF10 in chicken cells. We found that SRSF10 promoted both exon inclusion and exclusion. Functionally, many of SRSF10-verified alternative exons are linked to pathways of stress and apoptosis. Importantly, reconstituted SRSF10 in knockout cells recovered wild-type splicing patterns and considerably rescued the stress-related defects. Together, our results provide mechanistic insight into SRSF10-regulated alternative splicing events in vivo and demonstrate that SRSF10 plays a crucial role in cell survival under stress conditions. RNA-seq for wide type (WT) and SRSF10-deficient (KO) chicken DT40 cells

2014-01-22 | E-GEOD-53354 | biostudies-arrayexpress

Transcriptome analysis of alternative splicing events regulated by SRSF10 reveals position-dependent splicing modulation.

2014-01-22 | GSE53354 | GEO

Next Generation Sequencing Analysis of Wild Type and SRSF10-/- embryonic day 13.5 heart Transcriptomes

Project description:We generated the SRSF10 -/- mice, and collected their embryonic heart at 13.5 and controls. Then, we extracted RNAs of embryonic heart and performed next generation sequencing. By comparing sequcing data from WT and SRSF10 -/- samples, we profiled the alternative splicing events and gene expression regulated by SRSF10 during mouse heart development process. E13.5 embryonic heart mRNA profiles of wild type (WT) and SRSF10-/- mice were generated by deep sequencing, using Illumina HiSeq2000.

2015-04-01 | E-GEOD-66965 | biostudies-arrayexpress

Next Generation Sequencing Analysis of Wild Type and SRSF10-/- embryonic day 13.5 heart Transcriptomes

2015-04-01 | GSE66965 | GEO

A novel class of CLK inhibitors that targets SRSF10 and promote p53-mediated cytotoxicity on human colorectal cancer cells

Project description:The expression of the splicing regulator SRSF10 is elevated in metastatic colorectal cancer (CRC) where it promotes the production of the pro-tumorigenic Bclaf1-L splice variant. We discovered a group of small molecules with an aminothiazole carboxamide core (GPS167, GPS192 and others) that decrease production of Bclaf1-L. Additional alternative splicing events regulated by SRSF10 in HCT116 cells were affected by GPS167/192 (e.g. Mdm4 and Wtap), and other events also shifted in a SRSF10-independent manner (e.g. Mdm2, Nab2, Tra2a). GPS167/192 increased the interaction of SRSF10 with CLK1 and CLK4 kinases, leading us to show that GPS167/192 were CLK kinase inhibitors impacting the activity of SRSF10. Notably, GPS167 impaired the growth of colorectal cancer cell lines and organoids, inhibited anchorage-independent colony formation, cell migration and promoted cytoxicity that required SRSF10 and p53. The anti-cancer potential of this new class of CLK kinase inhibitors is further supported by the observation that GPS167 only minimally affected normal colonocytes and normal colorectal organoids. Thus, while SRSF10 promotes tumorigenesis, DNA damage promoted by GPS167 redirects SRSF10 activity towards cell death in a p53-dependent manner.

2020-06-30 | GSE153492 | GEO

A novel class of CLK kinases inhibitors that target SRSF10 and promote p53-mediated cytotoxicity on human colorectal cancer cells

Project description:The elevated expression of the splicing regulator SRSF10 in metastatic colorectal cancer (CRC) stimulates the production of the pro-tumorigenic Bclaf1-L splice variant. We discovered a group of small molecules with an aminothiazole carboxamide core (GPS167, GPS192 and others) that decrease production of Bclaf1-L. While additional alternative splicing events regulated by SRSF10 are affected by GPS167/192 in HCT116 cells (e.g., in MDM4, WTAP, SLK1 and CLK1), other events are shifted in a SRSF10-independent manner (e.g., in MDM2, NAB2 and TRA2A). GPS167/192 increased the interaction of SRSF10 with the CLK1 and CLK4 kinases, leading us to show that GPS167/192 are CLK kinase inhibitors preferentially impacting the activity of SRSF10. Notably, GPS167 impairs the growth of CRC cell lines and organoids, inhibits anchorage-independent colony formation, cell migration, and promotes cytoxicity that requires SRSF10 and p53. In contrast, GPS167 only minimally affects normal colonocytes and normal colorectal organoids. Thus, GPS167 reprograms the tumorigenic activity of SRSF10 in CRC cells to elicit p53-dependent apoptosis.

2021-06-15 | GSE161168 | GEO

A novel class of CLK kinases inhibitors that target SRSF10 and promote p53mediated cytotoxicity on human colorectal cancer cells

2021-09-09 | PXD022333 | Pride

SRSF10 is essential for progenitor spermatogonia expansion by regulating alternative splicing

Project description:Alternative splicing expands the proteome complexity and plays essential roles in tissue development and human diseases. However, how spermatogenesis is regulated by alternative splicing remains largely unknown. Here, using germ cell-specific knockout mouse model, we demonstrate that the splicing factor Srsf10 is essential for spermatogenesis and male fertility. Depletion of Srsf10 in germ cells had little effect on the formation of SSCs but impeded the expansion of progenitor spermatogonia, leading to the failure of spermatogonia differentiation and meiosis initiation. This was evidenced by the decreased expression of progenitor cell markers in bulk RNA-seq, and much less progenitor and differentiating spermatogonia in single-cell RNA-seq data. Furthermore, the expression of genes involved in cell cycle was abnormal in all subtypes of spermatogonia identified in single-cell RNA-seq data. Notably, using isolated spermatogonia, we found that Srsf10 depletion disturbed the alternative splicing of hundreds of genes, which were preferentially associated with cell cycle, mitotic cell cycle checkpoint and germ cell development, including Dazl, Kit, Ret, Sycp1, Nasp and Bora. These data suggest that SRSF10 is critical for the expansion of progenitor spermatogonia by regulating alternative splicing, expanding our understanding of the novel mechanism underlying spermatogenesis.

2022-11-07 | GSE190646 | GEO

BCLAF1 and its pre-mRNA splicing regulator SRSF10 both regulate tumorigenic capacity of human colon cancer cells

Project description:Bcl-2-accociated transcription factor 1(BCLAF1) has been shown to be involved in multiple biological processes. Transcript variants encoding different isoforms that are generated by alternative splicing have been found for this gene, but little is known about the mechanisms governing its splicing regulation and whether the misregulation is associated with cancer development. Mechanistic analysis revealed that splicing factor SRSF10 specifically interacts with exon5a and activates its inclusion, as RNAi-mediated knockdown of SRSF10 induced a dramatic skipping of exon5a. To define a comprehensive programm of alternative splicing that is regulated by SRSF10 in RKO cells, we used RNA-seq coupled with a bioinformatic analysis to identify the extensive splicing network regulated by SRSF10 in RKO cells.

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