PT-020 - FUNCTIONAL CHARACTERIZATION OF ELAVL2 REVEALED THE ROLE OF POST-TRANSCRIPTIONAL REGULATION IN PSYCHIATRIC DISORDERS AND ANTIDEPRESSANT TREATMENT RESPONSE.

T. Philips, H. Gao, T. Nguyen, D. Liu, R. Weinshilboum; Mayo Clinic, Rochester, MN, USA.

Background: ELAVL2 is a neuron-specific RNA-binding protein playing an important role in maintaining neuronal functions. ELAVL2 has been associated with numerous psychiatric disorders including substance use disorders (SUDs), major depressive disorder (MDD) and antidepressant treatment response in genome-wide association studies (GWAS). Molecular mechanism(s) for how ELAVL2 contributes to these GWAS phenotypes remain unknown.

Methods: We performed 3-phase studies with ELAVL2 using human neuronal cells, including (1) enhanced crosslinking immunoprecipitation sequencing (eCLIP-seq) to determine transcriptome-wide ELAVL2 RNA-binding sites; (2) RNA-seq using samples from two cell lines with ELAVL2 knock-down (KD); (3) integration of eCLIP-seq and RNA-seq data for discovery of ELAVL2 targeted genes and following-up annotation for their roles in psychiatric disorders.

Results: eCLIP-seq identified 8,237 peaks mapping to 2,820 genes in SK-N-FI neuroblastoma cells. 75% of those peaks mapped to 3’-untranslated regions (3’-UTRs) and 23% to introns. RNA-seq identified only 18 differentially expressed genes in both SK-N-FI and iPSC-derived neurons after ELAVL2 KD, indicating a limit impact of ELAVL2 on gene transcription. We next performed differential alternative polyadenylation (APA) analysis and identified 252 and 615 APA sites (FDR < 0.05) in SK-N-FI and iPSC-derived neurons. Overlap of those differential APA sites with eCLIP-seq data identified 354 ELAVL2-bound APA genes, many of which, such as OPRM1 and NCAM1, are known to function in SUDs and MDD.

Conclusion: We have generated transcriptome-wide data to help understand ELAVL2 function in human neuronal cells. Those data suggest a potentially important role for post-transcriptional gene regulation in psychiatric disorders and antidepressant treatment response.