Falcone, G. | bioRxiv Science

bioRxiv2018

Dysregulation of circular RNAs in myotonic dystrophy type 1

Circular RNAs (circRNAs) constitute a recently re-discovered class of non-coding RNAs functioning as sponge for miRNAs and proteins, affecting RNA splicing and regulating transcription. CircRNAs are generated by \"back-splicing\", linking covalently 3- and 5-ends of exons. Thus, circRNA levels might be deregulated in conditions associated to altered RNA-splicing. Indeed, increasing evidence indicates their role in human diseases. Specifically, myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG-repeats in the DMPK gene, resulting in abnormal mRNA-splicing. In this investigation, circRNAs expressed in DM1 skeletal muscles were identified by analyzing RNA-sequencing data-sets followed by qPCR validation. In muscle biopsies, out of 9 tested, 4 transcripts showed an increased circular fraction: CDYL, HIPK3, RTN4_03 and ZNF609. The circular fraction values correlated positively with skeletal muscle strength and Receiver-Operating-Characteristics curves showed that these four circRNAs allow to distinguish DM1 patients from controls. The identified circRNAs were also detectable in peripheral-blood-mononuclear-cells (PBMCs) and plasma of DM1 patients, but they were not regulated significantly, indicating a tissue-selectivity of the identified modulations. Finally, increased circular fractions of RTN4_03 and ZNF609 were also observed in differentiated myogenic cell lines derived from DM1 patients.\n\nIn conclusion, this proof-of-principle study identified circRNA dysregulation in DM1 patients.

molecular biology↗

bioRxiv2018

The Subtype Specificity of Genetic Loci Associated with Stroke in 16,664 cases and 32,792 controls

BackgroundGenome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischaemic and haemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes.\n\nMethodsWe performed Bayesian multinomial regression in 16,664 stroke cases and 32,792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under two commonly used stroke classification systems, Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS). All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel.\n\nResultsSixteen loci were considered for analysis. Seven loci influenced both haemorrhagic and ischaemic stroke, three of which influenced ischaemic and haemorrhagic subtypes under both TOAST and CCS. Under CCS, 4 loci influenced both small vessel stroke and intracerebral haemorrhage. An EDNRA locus demonstrated opposing effects on ischaemic and haemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction and only one locus (12q24) was predicted to influence all ischaemic stroke subtypes.\n\nConclusionsHeterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between haemorrhagic and ischaemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

genetics↗