Coding and non-coding RNA dysregulation in bipolar disorder

Abstract

office 4.127 (Stratenum), HP 4.205 | 3584 CG Utrecht | The Netherlands | +31 (0)88 75 68638 | j.luykx@umcutrecht.nl Word count abstract: 192 Word count manuscript: 3146 Number of figures: 3 Number of tables: 1 Running title: Coding and non-coding RNAs in bipolar disorder. AbstractThe molecular mechanisms underlying bipolar disorder (BPD) have remained largely unknown. Postmortem brain tissue studies comparing BPD patients with healthy controls have produced a heterogeneous array of potentially implicated protein-coding RNAs. We hypothesized that dysregulation of not only coding, but multiple classes of RNA (coding RNA, long non-coding (lnc) RNA, circular (circ) RNA, and/or alternative splicing) underlie the pathogenesis of BPD. Using nonpolyadenylated libraries we performed RNA sequencing in postmortem human medial frontal gyrus tissue from BPD patients and healthy controls. We found twenty genes, some of which not previously implicated in BPD, differentially expressed. PCR validation and replication confirmed the implication of these DE genes. Functional analyses identified enrichment of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, ten lncRNA transcripts were differentially expressed. Furthermore, we detected an overall increased number of alternative splicing events in BPD, as well as an increase in the number of genes carrying alternative splicing events. Finally, we report altered levels of two circular transcripts, cNEBL and cEPHA3. In conclusion, our non-coding RNA findings demonstrate that RNA dysregulation in BPD is not limited to coding regions, opening avenues for future pharmacological investigations and biomarker research.

The Secret Garden of Neuronal circRNAs

“…circRNA decoy activity for HUD might suggest a role of circHomer1 in the regulation of alternative splicing in normal and pathological conditions. Another recent study shows that the differential expression of circRNA observed in the frontal gyrus of patients with bipolar disorder is associated with an overall dysregulation of AS [109]. In the overall, studies reported in Table 2 suggest that, in psychiatric disorders, a circRNA general dysregulation correlates with a global change in AS [87,110,111].…”