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SRSF1 governs progenitor-specific alternative splicing to maintain adult epithelial tissue homeostasis and renewal

ABSTRACT: Alternative splicing generates distinct mRNA variants and is essential for development, homeostasis, and renewal. Proteins of the serine/arginine (SR)-rich splicing factor family are major splicing regulators that are broadly required for organ development as well as cell and organism viability. However, how these proteins support adult organ function remains largely unknown. Here, we used the continuously growing mouse incisor as a model to dissect the functions of the prototypical SR-family protein SRSF1 during tissue homeostasis and renewal. We identified an SRSF1-governed alternative splicing network that is specifically required for dental proliferation and survival of progenitors but dispensable for the viability of differentiated cells. We also observed a similar progenitor-specific role of SRSF1 in the small intestinal epithelium, indicating a conserved function of SRSF1 across adult epithelial tissues. Thus, our findings define a regulatory mechanism by which SRSF1 specifically controls progenitor-specific alternative splicing events to support adult tissue homeostasis and renewal.

ORGANISM(S): Mus musculus

PROVIDER: GSE193492 | GEO | 2022/01/18

REPOSITORIES: GEO

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SRSF1 governs progenitor-specific alternative splicing to maintain adult epithelial tissue homeostasis and renewal

Project description:SRSF1 governs progenitor-specific alternative splicing to maintain adult epithelial tissue homeostasis and renewal

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Genome-wide Analysis Reveals SR Protein Cooperation and Competition in Regulated Splicing

Project description:SR proteins are well-characterized RNA binding proteins that promote exon inclusion by binding to exonic splicing enhancers (ESEs). However, it has been unclear whether regulatory rules deduced on model genes apply generally to activities of SR proteins in the cell. Here, we report global analyses of two prototypical SR proteins SRSF1 (SF2/ASF) and SRSF2 (SC35) using splicing-sensitive arrays and CLIP-seq on mouse embryo fibroblasts (MEFs). Unexpectedly, we find that these SR proteins promote both inclusion and skipping of exons in vivo, but their binding patterns do not explain such opposite responses. Further analyses reveal that loss of one SR protein is accompanied by coordinated loss or compensatory gain in the interaction of other SR proteins at the affected exons. Therefore, specific effects on regulated splicing by one SR protein actually depend on a complex set of relationships with multiple other SR proteins in mammalian genomes. SRSF1 and SRSF2 CLIP-seq

2013-04-05 | E-GEOD-44591 | biostudies-arrayexpress

Translational activity of the splicing factor SRSF1 is required for development and cilia function

Project description:The SR protein family of splicing factors regulate constitutive and alternative pre-mRNA splicing. A subset of them, including SRSF1, shuttles continuously between the nucleus and cytoplasm affecting post-splicing processes. We have previously identified a role for SRSF1 in promoting the translation of specific mRNA transcripts, particularly those encoding centrosomal proteins. Here, we used CRISPR/Cas9 editing to knock-in a nuclear retention signal (NRS) in Srsf1 resulting in a non-shuttling SRSF1 mouse model (Srsf1NRS). Srsf1NRS/NRS mice displayed small body size, hydrocephaly and male infertility, all associated with ciliary defects. We observed reduced translation of thousands of mRNAs, in particular of ciliary components, in cells derived from this model. Consistently, we found that the lack of cytoplasmic SRSF1 led to decreased abundance of proteins involved in multiciliogenesis and affected ciliary structure and motility in multiciliated cells. Altogether, these results highlight the physiological relevance of the activity of a splicing factor in the cytoplasm.

2021-08-06 | PXD019859 | Pride

Splicing factor SRSF1 is essential for homing of precursor spermatogonial stem cells in mice

Project description:Spermatogonial stem cells (SSCs) provide a continuous spermatogenesis and male fertility. However, the underlying mechanisms of alternative splicing (AS) in mouse SSCs are still largely unclear. We demonstrated that SRSF1 is essential for gene expression and splicing in mouse SSCs. Specific deletion of Srsf1 in mouse germ cells impairs self-renewal and homing of SSCs leading to male infertility. Whole-mount staining data showed the absence of germ cells in the testes of adult cKO mice, which indicates severe non-obstructive azoospermia (NOA) in cKO mice. Expression of SSC-related genes (Gfra1, Pou5f1, Plzf, Dnd1, Stra8, and Taf4b) was significantly reduced in the testes of conditional knockout (cKO) mice. CLIP-seq data found that SSC-related genes (Plzf, Id4, Setdb1, Stra8, Tial1, Bcas2, Ddx5, Srsf10, Uhrf1, and Bud31) were bound by SRSF1 in the mouse testes. Moreover, multi-omics analysis suggests that SRSF1 directly binds and regulates the expression of Tial1 via AS to implement SSCs self-renewal and differentiation. Collectively, our data reveal the critical role of an SRSF1-mediated AS in SSCs self-renewal and differentiation, which may provide a framework to elucidate the molecular mechanisms of the post-transcriptional network underlying SSCs.

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SRSF1 role in cellular gene expression and splicing

Project description:SRSF1 is an abundant RNA-binding protein with functions in mRNA splicing, stability, translation and transcription of cellular and viral genes. We analyzed the role that SRSF1 plays in cellular gene transcription and splicing by transfecting HEK293 cells with a SRSF1 expression plasmid and by analyzing the transcriptome of the transiently transfected cells 15 hrs and 48 hrs post transfection. We also explored the role of the SRSF1 domains by transfecting a deletion clone of SRSF1 carrying only the RNA Recognition Motifs 1 and 2 (RRM1,2) but not the Arg-Ser rich (SR) domain.

2019-03-20 | GSE124397 | GEO

SRSF1-mediated alternative splicing is required for spermatogonial stem cell differentiation and mitotic-to-meiotic transition [LACE-seq]

Project description:Alternative splicing (AS) plays significant roles in fundamental biological activities. AS also are prevalent in the testis, but the regulations of alternative splicing in spermatogenesis is vague. Here, we report that Serine/arginine-rich splicing factor 1 (SRSF1), plays critical roles in alternative splicing and male reproduction. Male germ cell-specific deletion of Srsf1 led to complete infertility and abnormal spermatogenesis. We further demonstrated that Srsf1 is required for spermatogonial stem cell differentiation and mitotic-to-meiotic transition. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that SRSF1 regulatory networks have functions in spermatogenesis. Particularly, we found that SRSF1 affects the AS of Stra8 in a direct manner and Dazl, Dmc1, Mre11a, Syce2 and Rif1 in an indirect manner. Taken together, our findings demonstrate that SRSF1 has crucial functions in spermatogenesis and male fertility by regulating alternative splicing.

2024-03-31 | GSE226551 | GEO

SRSF1-mediated alternative splicing is required for spermatogonial stem cell differentiation and mitotic-to-meiotic transition [RNA-Seq]

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Project description:Analysis to identify genome-wide differential alternative splicing events in A549 cells in which the levels of the gene SRSF1 were down-regulated with a specific siRNA 9 samples from three independent experiments using A549 cells transfected with lipofectamine alone, scramble siRNA or SRSF1 siRNA

2013-12-18 | E-GEOD-53410 | biostudies-arrayexpress

Chip-chip from Mouse MEFs cells for H3K36me3, Srsf1, Psip1(A300-847 antibody).

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