We studied the role of protein Rbfox2 in alternative splicing during muscle differentiation. Using iCLIP protein-RNA interaction data and RNA-seq data we were able to show that 30% of observed splicing transitions during myogenesis are regulated by Rbfox2. We showed that this single RNA binding protein regulates the splicing and transcription of two important targets: Mef2d modulates transcription and Rock2 regulates cell signaling. Both programs are key regulators of tissue-specific functions during developmental changes.
COBISS.SI-ID: 1536022723
We have developed and proposed a method for the identification of clusters of repetitive short RNA motifs occuring around alternatively expressed exons. We applied the method to identify the RNA sequence motifs for a number of RNA-binding proteins (hnRNP C, PTBP1, TDP-43, TIA1, TIAL1). While the positional distribution was similar for the various proteins, the identifed sequences and effect of RNA-binding proteins on splicing of their target RNAs differed. By comparing alternatively spliced exons in brain and heart we identified known and new motifs associated with RNA-binding proteins that regulate alternative splicing.
COBISS.SI-ID: 31140057
This is an invited scientific commentary by the elite journal Brain on their publication ‘Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers’ by Freischmidt et al. Defective RNA processing has occupied centre stage in the pathogenesis of amyotrophic lateral sclerosis (ALS) since the identification of TARDBP (also known as TDP-43) inclusions in 95% of cases and pathogenic mutations in RNA processing genes such as TARDBP, FUS and MATR3 (Sreedharan et al., 2008; Vance et al., 2009; Johnson et al., 2014). FUS and TARDBP are known to regulate mRNA transcription, splicing, stability and transport (Tollervey et al., 2011; Rogelj et al., 2012) but they are also part of the large Drosha complex that regulates microRNA (miRNA) biogenesis (Gregory et al., 2004). Dysregulation of miRNA expression has been shown in many cancers and more recently in Alzheimer’s disease and is predicted to play a mechanistic role and/or be an indirect biomarker of disease. Freischmidt et al. (2014) report that levels of a specific subset of miRNAs are reduced in the serum of patients with familial and sporadic ALS, and that these reductions are even detectable in presymptomatic carriers of pathogenic ALS mutations. If these results can be replicated in larger cohorts then this will become a landmark study.
COBISS.SI-ID: 28055335