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Splice isoform-perturbation coupled to single cell transcriptome profiling reveals functions of microexons in neurogenesis and autism-linked pathways [RNA-seq]

ABSTRACT: A major challenge of biomedical research is to assign functions to the myriad alternative RNA and protein isoforms. This challenge is particularly relevant to the mammalian nervous system, which produces complex repertoires of alternative splicing events. Here, we describe CHyMErA-seq, a platform that couples systematic deletion of exons to a single cell transcriptomics read-out, and apply this method to investigate a critical program of brain-specific microexons. Perturbation of microexons during neurogenesis reveals convergent roles in the temporal regulation of gene expression programs that direct signalling pathways and morphogenesis. We further observe microexons, including those in the Bin1, Clasp1, Gfra1, Med23, Ptprf and Ralgapb genes, that are required for the correct timing of autism-linked gene expression. Collectively, we describe a flexible system for isoform-resolution perturbation at a single cell level, together with insights into the roles of microexons in the developmental timing of neurogenesis transcriptomic signatures linked to brain disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE291608 | GEO | 2025/11/28

REPOSITORIES: GEO

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Splice isoform-perturbation coupled to single cell transcriptome profiling reveals functions of microexons in neurogenesis and autism-linked pathways [snRNA-Seq]

Project description:A major challenge of biomedical research is to assign functions to the myriad alternative RNA and protein isoforms. This challenge is particularly relevant to the mammalian nervous system, which produces complex repertoires of alternative splicing events. Here, we describe CHyMErA-seq, a platform that couples systematic deletion of exons to a single cell transcriptomics read-out, and apply this method to investigate a critical program of brain-specific microexons. Perturbation of microexons during neurogenesis reveals convergent roles in the temporal regulation of gene expression programs that direct signalling pathways and morphogenesis. We further observe microexons, including those in the Bin1, Clasp1, Gfra1, Med23, Ptprf and Ralgapb genes, that are required for the correct timing of autism-linked gene expression. Collectively, we describe a flexible system for isoform-resolution perturbation at a single cell level, together with insights into the roles of microexons in the developmental timing of neurogenesis transcriptomic signatures linked to brain disorders.

2025-11-28 | GSE291610 | GEO

Comprehensive identification and alternative splicing of microexons in Drosophila

Project description:Interrupted exons in the pre-mRNA transcripts are ligated together through RNA splicing, which plays critical roles in the regulation of gene expression. Exons with length ≤30 nt are defined as microexons that are unique in identifications and gene functions. However, due to difficulties in mapping short segments from sequencing reads, microexons especially shorter than 8 nt, have not been well studied in many organisms. Here, we analyzed mRNA-seq data from a variety of Drosophila samples by a new developed bioinformatic tool, ce-TopHat. In addition to the Flybase annotated, 465 new microexons were identified. Differentially alternatively spliced (AS) microexons were investigated between the Drosophila tissues (head, body and gonad) and genders. Most of the AS microexons are found in the head, as well as two AS microexons were identified in the sex-determination pathway gene fruitless.

2021-04-20 | GSE163147 | GEO

Origin and evolution of neural microexons

Project description:The mechanisms by which entire programs of gene regulation emerged during evolution are poorly understood. Neuronal microexons represent the most conserved class of alternative splicing in vertebrates and are critical for proper brain development and function. Here, we discover neural microexon programs in non-vertebrate species and trace their origin to bilaterian ancestors through the emergence of a previously uncharacterized ‘enhancer of microexons' (eMIC) protein domain. The eMIC domain originated as an alternative, neural-enriched splice isoform of the pan-eukaryotic Srrm2/SRm300 splicing factor gene, and subsequently became fixed in the vertebrate and neuronal-specific splicing regulator Srrm4/nSR100 and its paralog Srrm3. Remarkably, the eMIC domain is necessary and sufficient for microexon splicing, and functions by interacting with the earliest components required for exon recognition. The emergence of a novel domain with restricted expression in the nervous system thus resulted in the evolution of splicing programs that contributed to qualitatively expand neuronal molecular complexity in bilaterians.

2019-03-12 | PXD010034 | Pride

Genome-wide CRISPR-Cas9 interrogation of splicing networks reveals a mechanism for recognition of autism-misregulated neuronal microexons [SPAR-seq]

Project description:Alternative splicing has critical roles in diverse cellular, developmental and pathological processes. However, the full repertoires of factors that control individual splicing events are not known. We describe a CRISPR-based screening strategy for the systematic identification of genes that control 3-27 nt microexons with functions in nervous system development and that are commonly disrupted in autism. Besides known regulators including nSR100/Srrm4, Rbfox and Ptbp1, approximately 200 additional genes impact microexon splicing. These genes are enriched in genetic links to autism. Two of the screen hits, Srsf11 and Rnps1, preferentially regulate Srrm4-dependent microexons relative to other exons. These factors form mutually stabilizing interactions with Srrm4 that bridge upstream intronic enhancer elements and exonic sequences to activate microexon splicing. Our study thus presents a system for the genome-wide definition of splicing regulatory networks and further reveals a mechanism for the recognition of microexons with critical roles in nervous system development and disorders.

2018-10-12 | GSE120164 | GEO

Genome-wide CRISPR-Cas9 interrogation of splicing networks reveals a mechanism for recognition of autism-misregulated neuronal microexons [RNA-seq]

2018-10-12 | GSE112600 | GEO

Genome-wide CRISPR-Cas9 interrogation of splicing networks reveals a mechanism for recognition of autism-misregulated neuronal microexons [CRISPR screen]

2018-10-12 | GSE112599 | GEO

Genome-wide CRISPR-Cas9 interrogation of splicing networks reveals a mechanism for recognition of autism-misregulated neuronal microexons [CLIP-seq]

2018-10-12 | GSE112598 | GEO

Phenotypic impact of individual conserved neuronal microexons and their regulators in zebrafish

Project description:Microexons show remarkable neuronal switch-like regulation and evolutionary conservation and they can impact protein-protein interactions and other molecular functions. Neuronal microexons are regulated in a tightly coordinated manner by the splicing factors Srrm3 and Srrm4. Depletion of Srrm3/4 in mice causes dramatic neurological phenotypes and their misregulation is associated with human disease. However, which microexon targets are associated with these phenotypes and how individual microexon deletions could impact neurodevelopment, physiology and behavior is unknown. To address this question, we generated zebrafish KO lines for 18 individual microexons and characterized their phenotypes at multiple levels, together with srrm3/4 mutant lines. We found that, while mutation of the regulators, specially srrm3, shows multiple alterations in neuritogenesis, locomotion and social behavior, the impact of deleting of individual microexons was usually mild or non-existing. Nonetheless, for various microexons, we identified neuritogenesis defects (evi5b, vav2, itsn1, src) and social defects (vti1a, kif1b). In addition, microexon deletions led to transcriptomic alterations that are likely compensatory. Overall, our data suggest that the defects caused by srrm3/4 depletion are due to a cumulative effect of multiple small impacts that can individually be well tolerated by zebrafish.

2025-10-31 | GSE278690 | GEO

Regulation of retina microexons by srrm3 in zebrafish

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.

2022-07-01 | GSE180778 | GEO

Autism-misregulated eIF4G microexons control synaptic translation and higher-order cognitive functions [Ribo-Seq]

Project description:Microexons represent the most highly conserved class of alternative splicing, yet their functions are poorly understood. Here, we focus on closely related neuronal microexons overlapping prion-like domains in the translation initiation factors, eIF4G1 and eIF4G3, the splicing of which is activity-dependent and frequently disrupted in autism. CRISPR-Cas9 deletion of these microexons selectively up-regulates synaptic proteins that control neuronal activity and plasticity and further triggers a gene expression program mirroring that of activated neurons. Mice lacking the Eif4g1 microexon display social behavior, learning and memory deficits, as well as alterations in hippocampal synaptic plasticity. The eIF4G microexons appear to reduce synaptic protein synthesis by causing ribosome stalling, through a mechanism whereby they promote the coalescence of cytoplasmic granule components associated with translation repression, including the Fragile X mental retardation protein, FMRP. The results thus reveal an autism-disrupted mechanism by which alternative splicing specializes translation to control higher-order cognitive functioning.

2020-01-30 | GSE141599 | GEO

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