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STRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells

ABSTRACT: STRAP protein was IP'd and corresponding binding proteins were identified by high resolution nanoLCMS2 vs a control experiment.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Primary Cell, Embryonic Stem Cell

DISEASE(S): Disease Free

SUBMITTER: james mobley

LAB HEAD: james mobley

PROVIDER: PXD015371 | Pride | 2020-09-10

REPOSITORIES: Pride

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			Action	DRS
	Mudpit_jm_201501118_LinJin_IgG1.mzid.gz	Mzid
	Mudpit_jm_201501118_LinJin_IgG1.mzid_Mudpit_jm_201501118_LinJin_IgG1.MGF	Mzid
	Mudpit_jm_201501118_LinJin_IgG1.mzid_Mudpit_jm_201501118_LinJin_IgG1.pride.mgf.gz	Mzid
	Mudpit_jm_201501118_LinJin_IgG1.pride.mztab.gz	Mztab
	Mudpit_jm_201501118_LinJin_STRAP1.mzid.gz	Mzid

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Publications

STRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells.

Jin Lin L Chen Yunjia Y Crossman David K DK Datta Arunima A Vu Trung T Mobley James A JA Basu Malay Kumar MK Scarduzio Mariangela M Wang Hengbin H Chang Chenbei C Datta Pran K PK

Nature communications 20201123 1

Alternative splicing (AS) is involved in cell fate decisions and embryonic development. However, regulation of these processes is poorly understood. Here, we have identified the serine threonine kinase receptor-associated protein (STRAP) as a putative spliceosome-associated factor. Upon Strap deletion, there are numerous AS events observed in mouse embryoid bodies (EBs) undergoing a neuroectoderm-like state. Global mapping of STRAP-RNA binding in mouse embryos by enhanced-CLIP sequencing (eCLIP- ...[more]

PMID: 33230114

Similar Datasets

STRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells.

Project description:Alternative splicing (AS) is involved in cell fate decisions and embryonic development. However, regulation of these processes is poorly understood. Here, we have identified the serine threonine kinase receptor-associated protein (STRAP) as a putative spliceosome-associated factor. Upon Strap deletion, there are numerous AS events observed in mouse embryoid bodies (EBs) undergoing a neuroectoderm-like state. Global mapping of STRAP-RNA binding in mouse embryos by enhanced-CLIP sequencing (eCLIP-seq) reveals that STRAP preferably targets transcripts for nervous system development and regulates AS through preferred binding positions, as demonstrated for two neuronal-specific genes, Nnat and Mark3. We have found that STRAP involves in the assembly of 17S U2 snRNP proteins. Moreover, in Xenopus, loss of Strap leads to impeded lineage differentiation in embryos, delayed neural tube closure, and altered exon skipping. Collectively, our findings reveal a previously unknown function of STRAP in mediating the splicing networks of lineage commitment, alteration of which may be involved in early embryonic lethality in mice.

| S-EPMC7684319 | biostudies-literature

Next generation sequencing facilitates quantitative analysis of STRAP-dependent alternative splicing events

Project description:We report the application of next generation sequencing for evaluating alternative splicing (AS) events on lineage-committed WT and Strap-KO embryoid body (EB) cells. We also analyzed AS during mouse embryo development using RNA-seq data. Of all STRAP-regulated AS, exon-skipping events were the most frequent ones with significant changes in 49% (240 out of 489) cases. Retained introns were also overrepresented (20%, 97 out of 489) as compared to other types of AS STRAP appears to function in promoting both exon inclusion and skipping at different exons. GO function revealed STRAP-regulated AS events involve in protein catabolism, molecular binding and cell motility. More specifically, they included neuronal migration and development. Together, these analyses uncovered the previous unknown role of STRAP involved in the substantial transcriptional diversity at the exon level in certain development stage. Our study also represents the first detailed analysis of AS events in the mouse early organogenesis with biologic replicates, generated by RNA-seq technology.

2020-09-16 | GSE131471 | GEO

STRAP-dependent alternative splicing events STRAP-RNA interactions in mouse early embryo and lineage-committed cells.

Project description:STRAP-dependent alternative splicing events STRAP-RNA interactions in mouse early embryo and lineage-committed cells.

| PRJNA543786 | ENA

Exon sequences at the splice junctions affect splicing fidelity and alternative splicing.

Project description:Identification of splice sites is essential for the expression of most eukaryotic genes, allowing accurate splicing of pre-mRNAs. The splice sites are recognized by the splicing machinery based on sequences within the pre-mRNA. Here, we show that the exon sequences at the splice junctions play a significant, previously unrecognized role in the selection of 3' splice sites during the second step of splicing. The influence of the exon sequences was enhanced by the Prp18 mutant Prp18DeltaCR, and the strength of an exon sequence in Prp18DeltaCR splicing predicted its effect in wild-type splicing. Analysis of the kinetics of splicing in vitro demonstrated that 3' splice sites were chosen competitively during the second step, likely at the same time as exon ligation. In wild-type yeast, splice site selection for two genes studied was altered by point mutations in their exon bases, affecting splicing fidelity and alternative splicing. Finally, we note that the degeneracy of the genetic code allows competing 3' splice sites to be eliminated from coding regions, and we suggest that the evolution of the splicing signals and the genetic code are connected.

| S-EPMC2776460 | biostudies-literature

Transcriptional analysis of early lineage commitment in human embryonic stem cells.

Project description:The mechanisms responsible for the maintenance of pluripotency in human embryonic stem cells, and those that drive their commitment into particular differentiation lineages, are poorly understood. In fact, even our knowledge of the phenotype of hESC is limited, because the immunological and molecular criteria presently used to define this phenotype describe the properties of a heterogeneous population of cells.We used a novel approach combining immunological and transcriptional analysis (immunotranscriptional profiling) to compare gene expression in hESC populations at very early stages of differentiation. Immunotranscriptional profiling enabled us to identify novel markers of stem cells and their differentiated progeny, as well as novel potential regulators of hESC commitment and differentiation. The data show clearly that genes associated with the pluripotent state are downregulated in a coordinated fashion, and that they are co-expressed with lineage specific transcription factors in a continuum during the early stages of stem cell differentiation.These findings, that show that maintenance of pluripotency and lineage commitment are dynamic, interactive processes in hESC cultures, have important practical implications for propagation and directed differentiation of these cells, and for the interpretation of mechanistic studies of hESC renewal and commitment. Since embryonic stem cells at defined stages of commitment can be isolated in large numbers by immunological means, they provide a powerful model for studying molecular genetics of stem cell commitment in the embryo.

| S-EPMC1829156 | biostudies-literature

Fam40b is required for lineage commitment of murine embryonic stem cells.

Project description:FAM40B (STRIP2) is a member of the striatin-interacting phosphatase and kinase (STRIPAK) complex that is involved in the regulation of various processes such as cell proliferation and differentiation. Its role for differentiation processes in embryonic stem cells (ESCs) is till now completely unknown. Short hairpin RNA (shRNA)-mediated silencing of Fam40b expression in ESCs and differentiating embryoid bodies (EBs) led to perturbed differentiation to embryonic germ layers and their derivatives including a complete abrogation of cardiomyogenesis. Pluripotency factors such as Nanog, Oct4 and Sox2 as well as epigenetic factors such as histone acetyltransferase type B (HAT1) and DNA (cytosine-5)-methyltransferase 3-β (Dnmt3b) were highly upregulated in Fam40b knockdown EBs as compared with control and scrambled EBs. To examine the relevance of Fam40b for development in vivo, Fam40b was knocked down in developing zebrafish. Morpholino-mediated knockdown of Fam40b led to severe abnormalities of the cardiovascular system, including an impaired expression of ventricular myosin heavy chain (vmhc) and of cardiac myosin light chain 2 (cmlc2) in the heart. We identified the gene product of Fam40b in ESCs as a perinuclear and nucleolar protein with a molecular weight of 96 kDa. We conclude that the expression of Fam40b is essential for the lineage commitment of murine embryonic stem cells (mESCs) into differentiated somatic cells via mechanisms involving pluripotency and epigenetic networks.

| S-EPMC4123067 | biostudies-literature

Snail1-dependent control of embryonic stem cell pluripotency and lineage commitment.

Project description:Embryonic stem cells (ESCs) exhibit the dual properties of self-renewal and pluripotency as well as the ability to undergo differentiation that gives rise to all three germ layers. Wnt family members can both promote ESC maintenance and trigger differentiation while also controlling the expression of Snail1, a zinc-finger transcriptional repressor. Snail1 has been linked to events ranging from cell cycle regulation and cell survival to epithelial-mesenchymal transition (EMT) and gastrulation, but its role in self-renewal, pluripotency or lineage commitment in ESCs remains undefined. Here we demonstrate using isogenic pairs of conditional knockout mouse ESCs, that Snail1 exerts Wnt- and EMT independent control over the stem cell transcriptome without affecting self-renewal or pluripotency-associated functions. By contrast, during ESC differentiation, an endogenous Wnt-mediated burst in Snail1 expression regulates neuroectodermal fate while playing a required role in epiblast stem cell exit and the consequent lineage fate decisions that define mesoderm commitment.

| S-EPMC4115678 | biostudies-literature

Control of embryonic stem cell lineage commitment by core promoter factor, TAF3.

Project description:Deciphering the molecular basis of pluripotency is fundamental to our understanding of development and embryonic stem cell function. Here, we report that TAF3, a TBP-associated core promoter factor, is highly enriched in ES cells. In this context, TAF3 is required for endoderm lineage differentiation and prevents premature specification of neuroectoderm and mesoderm. In addition to its role in the core promoter recognition complex TFIID, genome-wide binding studies reveal that TAF3 localizes to a subset of chromosomal regions bound by CTCF/cohesin that are selectively associated with genes upregulated by TAF3. Notably, CTCF directly recruits TAF3 to promoter distal sites and TAF3-dependent DNA looping is observed between the promoter distal sites and core promoters occupied by TAF3/CTCF/cohesin. Together, our findings support a new role of TAF3 in mediating long-range chromatin regulatory interactions that safeguard the finely-balanced transcriptional programs underlying pluripotency.

| S-EPMC3191068 | biostudies-literature

A network of DZF proteins controls alternative splicing regulation and fidelity.

Project description:Proteins containing DZF (domain associated with zinc fingers) modules play important roles throughout gene expression, from transcription to translation. Derived from nucleotidyltransferases but lacking catalytic residues, DZF domains serve as heterodimerization surfaces between DZF protein pairs. Three DZF proteins are widely expressed in mammalian tissues, ILF2, ILF3 and ZFR, which form mutually exclusive ILF2-ILF3 and ILF2-ZFR heterodimers. Using eCLIP-Seq, we find that ZFR binds across broad intronic regions to regulate the alternative splicing of cassette and mutually exclusive exons. ZFR preferentially binds dsRNA in vitro and is enriched on introns containing conserved dsRNA elements in cells. Many splicing events are similarly altered upon depletion of any of the three DZF proteins; however, we also identify independent and opposing roles for ZFR and ILF3 in alternative splicing regulation. Along with widespread involvement in cassette exon splicing, the DZF proteins control the fidelity and regulation of over a dozen highly validated mutually exclusive splicing events. Our findings indicate that the DZF proteins form a complex regulatory network that leverages dsRNA binding by ILF3 and ZFR to modulate splicing regulation and fidelity.

| S-EPMC10325889 | biostudies-literature

Sex-specific and lineage-specific alternative splicing in primates.

Project description:Comparative studies of gene regulation suggest an important role for natural selection in shaping gene expression patterns within and between species. Most of these studies, however, estimated gene expression levels using microarray probes designed to hybridize to only a small proportion of each gene. Here, we used recently developed RNA sequencing protocols, which sidestep this limitation, to assess intra- and interspecies variation in gene regulatory processes in considerably more detail than was previously possible. Specifically, we used RNA-seq to study transcript levels in humans, chimpanzees, and rhesus macaques, using liver RNA samples from three males and three females from each species. Our approach allowed us to identify a large number of genes whose expression levels likely evolve under natural selection in primates. These include a subset of genes with conserved sexually dimorphic expression patterns across the three species, which we found to be enriched for genes involved in lipid metabolism. Our data also suggest that while alternative splicing is tightly regulated within and between species, sex-specific and lineage-specific changes in the expression of different splice forms are also frequent. Intriguingly, among genes in which a change in exon usage occurred exclusively in the human lineage, we found an enrichment of genes involved in anatomical structure and morphogenesis, raising the possibility that differences in the regulation of alternative splicing have been an important force in human evolution.

| S-EPMC2813474 | biostudies-literature

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