Core splicing architecture and early spliceosomal recognition determine microexon sensitivity to SRRM3/4
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1155178 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30504400_1.fastq.gz | Fastqsanger.gz | |||
| SRR30504400_2.fastq.gz | Fastqsanger.gz | |||
| SRR30504401_1.fastq.gz | Fastqsanger.gz | |||
| SRR30504401_2.fastq.gz | Fastqsanger.gz | |||
| SRR30504402_1.fastq.gz | Fastqsanger.gz |
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Project description:Microexons are essential for proper functioning of neurons and pancreatic endocrine cells, where their inclusion depends on the splicing factors SRRM3/4. However, in pancreatic cells, their lower expression limits inclusion to only the most sensitive neuronal microexons. Although various cis-acting elements are known to contribute to microexon regulation, how they determine this differential dose response and sensitivity to SRRM3/4 remains unknown. Here, through Massively Parallel Splicing Assays probing 28,535 variants, we found that sensitivity to SRRM4 is conserved across vertebrates and overall consistent with a regulatory model whereby the main determinants of microexon sensitivity are related to differences in the interplay between core splicing architecture and length constraints. This conclusion is further supported by distinct spliceosome activity in the absence of SRRM3/4 and by a mathematical model that assumes that the two types of microexons differ only in their efficiency of recruitment of early spliceosomal components.
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Project description:Microexons (exons ≤30 nts) are important features of neuronal transcriptomes, but pose mechanistic challenges to the splicing machinery. We previously showed that PRP-40, a component of the U1 spliceosome, is globally required for microexon splicing in C. elegans. Here we show that the homologous PRPF40A is also globally required for microexon splicing in mouse neuroblastoma cells. We find that PRPF40A co-regulates microexons along with SRRM4, a neuron-specific regulator of microexon splicing. The relationship between exon size and dependence on PRPF40A/SRRM4 is distinct, with SRRM4-dependence exhibiting a size threshold (~30 nts) and PRPF40A-dependence exhibiting a graded decrease as exon size increases. Finally, we show that PRPF40A knockdown causes an increase in productive splicing of its spliceosomal binding partner Luc7l by skipping of a small “poison exon.” Similar homeostatic cross-regulation is often observed across paralogous RNA binding proteins. Here we find this concept likewise applies across evolutionarily unrelated but functionally and physically coupled spliceosomal components.
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Project description:Pancreatic islets control glucose homeostasis by the balanced secretion of insulin and other hormones, and its abnormal function causes diabetes or hypoglycemia. Here, we uncover a conserved program of alternative microexons included in mRNAs of islet cells, particularly in genes involved in vesicle transport and exocytosis. Islet microexons (IsletMICs) are regulated by the RNA binding protein SRRM3 and represent a subset of the larger neural program that are particularly sensitive to the levels of this protein. Both SRRM3 and IsletMICs are induced by elevated glucose levels, and depletion of SRRM3 in beta cell lines and mouse islets, or repression of particular IsletMICs using antisense oligonucleotides, leads to inappropriate insulin secretion. Consistently, SRRM3 mutant mice display defects in islet cell identity and function, leading to hyperinsulinemic hypoglycemia. Importantly, human genetic variants that influence SRRM3 expression and microexon inclusion in islets are associated with fasting glucose variation and type 2 diabetes risk.
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Project description:Pancreatic neuroendocrine tumours (PanNETs) are a heterogeneous group of neoplasms arising in pancreatic islets and altering the hormone secreting function of neuroendocrine cells. Genome wide approaches have revealed the genomic landscape of PanNETs but have not explained their problematic hormone secretion. We show here that alternative splicing (AS) deregulation is responsible for changes in the secretory ability of PanNET cells. We reveal that the RNA binding protein SRRM3 is upregulated in PanNETs and favours the inclusion of a group of alternative microexons in certain mRNAs. These microexons are part of a larger neural program regulated by SRRM3 and their inclusion results in protein isoforms that change stimulus-induced insulin trafficking and secretion. By downregulating SRRM3 or inhibiting its binding on three of the microexon bearing pre-mRNAs, in animal and cellular PanNET models, we prove the necessity of SRRM3 for hormone secretion, PanNET progression and the enhanced neural component of PanNET tumours.
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Project description:Genes encoding RNA splicing factors are frequently mutated in clonal hematopoesis and diverse cancers. Most spliceosomal mutations affect specific hotspot residues, causing changes in exon and splice site recognition that promote disease. However, a subset of patients carry splicesomal mutations in non-hotspot residues, and their contribution to disease are unknown. Here we systematically characterized the function of several rare and private spliceosomal mutations in order to determine their potential disease relevance. We discovered that several rare and private spliceosomal mutations phenocopy the mechanistic splicing alterations induced by their "hotspot" counterparts. Our data suggest that many rare and private spliceosomal mutations contribute to disease pathogenesis.
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Project description:To investigate the role of srrm3 as a regulator of retina microexons (RetMICs) we have sequenced adult retina from WT animals, and enucleated eyes from 5 dpf larvae WT and KO for srrm3.
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Project description:The Bronx waltzer mutation in Srrm4, a gene that encodes a neuronal Ser/Arg (SR)-rich splicing factor, disrupts the expression of several alternative exons specifically in the inner ear. Here we show that the expression of SRRM3 in neurons limits the distribution of SRRM4-dependent splicing. In vitro, SRRM3 and SRRM4 regulated the same alternative exons, yet in vivo Srrm3 deficiency caused neuronal splicing alterations and motor dysfunction, indicating that SRRM3 has non-redundant functions. Mice harboring mutations in both Srrm3 and Srrm4 failed to breathe, and their neuromuscular junctions (NMJ) were malformed. Transcriptome-wide analysis revealed a large network of SRRM3/SRRM4-dependent splicing changes, including the skipping of key exons in the NMJ organizer Agrin. Furthermore, SRRM3/SRRM4 regulated gene expression through neuron-specific switches in chromatin regulatory complexes and by altering the reading frame in several mRNAs. Our findings reveal that the SRRM3/SRRM4 subfamily of SR proteins is central to regulation of the neuronal transcriptome. In this dataset, we include probe-set level data obtained from cerebellar samples. The processed data represent probe-set intensities that have been normalized to gene expression levels.
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Project description:The Bronx waltzer mutation in Srrm4, a gene that encodes a neuronal Ser/Arg (SR)-rich splicing factor, disrupts the expression of several alternative exons specifically in the inner ear. Here we show that the expression of SRRM3 in neurons limits the distribution of SRRM4-dependent splicing. In vitro, SRRM3 and SRRM4 regulated the same alternative exons, yet in vivo Srrm3 deficiency caused neuronal splicing alterations and motor dysfunction, indicating that SRRM3 has non-redundant functions. Mice harboring mutations in both Srrm3 and Srrm4 failed to breathe, and their neuromuscular junctions (NMJ) were malformed. Transcriptome-wide analysis revealed a large network of SRRM3/SRRM4-dependent splicing changes, including the skipping of key exons in the NMJ organizer Agrin. Furthermore, SRRM3/SRRM4 regulated gene expression through neuron-specific switches in chromatin regulatory complexes and by altering the reading frame in several mRNAs. Our findings reveal that the SRRM3/SRRM4 subfamily of SR proteins is central to regulation of the neuronal transcriptome. In this dataset, we include probe-set level data obtained from brain cortex samples. The processed data represent probe-set intensities that have been normalized to gene expression levels.
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