A highly conserved program of neuronal microexons is misregulated in autistic brains

By Manuel Irimia, Robert J. Weatheritt, J. Ellis, Neelroop Parikshak, Thomas Gonatopoulos-Pournatzis, Mariana Babor, Mathieu Quesnel-Vallières, Javier Tapial, Bushra Raj, D. O’Hanlon and 7 more. Cell, 2014

652 citations recorded by the source corpus.

Summary Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide ‘microexons’ display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein interaction networks during neurogenesis, the misregulation of which is linked to autism.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/50b56e7b67ca01c7c25009821818d9e4a479c378

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In Molecular Biology

Citations in the corpus

Predicting Splicing from Primary Sequence with Deep Learning. (2019, background): “…Arises from Weak Cryptic Splice Variants Alternative splicing is a major mode of gene regulation that serves to increase the diversity of transcripts in different tissues and developmental stages, and its dysregulation is associated with disease processes (Irimia et al., 2014; Wang et al., 2008).”
Alternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution. (2019, background): “In contrast to longer neurally regulated exons that are enriched within IDRs, as described above, neural microexons significantly overlap or are adjacent to modular domains that function in mediating protein and other ligand interactions (Irimia et al., 2014).”
Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016, neutral): “…differential splicing events in ASD. j , Clustering dendrogram and heat map for neuronal splicing factor gene expression levels across samples demonstrating three major clusters and the known positive correlation between SRRM4 and RBFOX1 and anticorrelation between PTBP1 and SRRM4 (refs 14,19).”
Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018, neutral): “Finally, several studies have demonstrated that genes carrying microexons are preferentially expressed in the brain and their splicing is dysregulated in ASD (30, 82, 83).”
GENCODE reference annotation for the human and mouse genomes (2018, background): “We have also completed an effort to capture all recently described unannotated microexons (18) into GENCODE, and further added an additional 146 novel microexons mined from public SLRseq data (19).”
RNA Sequencing Data: Hitchhiker's Guide to Expression Analysis (2018, neutral): “Transcriptomic studies identified previously unknown phenomena, such as microexons [27], cryptic exons [28], “skiptic” exons [29], circular RNAs [30], enhancer RNAs [31], fusion genes [32] and so-called epi-transcriptomics involving RNA base modifications [33].”
SUPPA2: fast, accurate, and uncertainty-aware differential splicing analysis across multiple conditions (2018, neutral): “These results are in agreement with the previously observed enrichment of microexon inclusion in differentiated neurons [22, 23].”