PT-002 - POST-TRANSCRIPTIONAL GENE REGULATION AND ANTIDEPRESSANT TREATMENT RESPONSE: FUNCTIONAL CHARACTERIZATION OF ELAVL2 RNA-BINDING PROTEIN IN IPSC-DERIVED NEURONS.

A. Saleh¹, H. Gao², X. Zhu³, R. Weinshilboum², D. Liu²; ¹Mayo Clinic, Mayo Clinic, Rochester, MN, USA, ²Mayo Clinic, ³Mayo Clinic, Mayo Clinic, Rochester, MN.

Background: The embryonic lethal and abnormal vision-like 2 (ELAVL2) gene is expressed exclusively in neurons and encodes an RNA-binding protein (RBP) that functions in post-transcriptional gene regulation (PTGR), e.g., RNA splicing and polyadenylation. Single-nucleotide polymorphisms (SNPs) mapping to ELAVL2 have been identified in genome-wide association studies (GWAS) for multiple psychiatry disorders and antidepressant treatment response. However, molecular mechanisms by which ELAVL2 is involved in these GWAS phenotypes remain unknown.

Methods: We generated human induced pluripotent stem cell (iPSC)-derived neurons to study ELAVL2 functions. Enhanced crosslinking and immunoprecipitation sequencing (eCLIP-seq) was performed to identify transcriptome-wide ELAVL2-RNA-bound loci. ELAVL2 was knocked-down and RNA-seq was performed to identify genes regulated by ELAVL2. Finally, these ELAVL2-regulated genes were overlapped with SNPs associated with GWAS psychiatric phenotypes to identify gene(s) that might contribute to psychiatric disorders and antidepressant treatment responses through ELAVL2-mediated PTGR.

Results: The eCLIP-seq identified 40,238 ELAVL2-bound sites (log2 Fold Enrichment ≥ 3, FDR < 0.05) that mapped to 6,166 genes, 74% of which mapped to 3’-untranslated regions (3’-UTR). RNA-seq identified 963 ELAVL2-bound genes that displayed changes in polyadenylation and 66 in splicing, but only 18 genes demonstrated changes in RNA levels after ELAVL2 knock-down. We identified 61 ELAVL2-bound loci which contained SNPs that were significantly associated with GWAS psychiatric phenotypes, phenotypes that included major depressive disorders (MDD) and antidepressant treatment response, bipolar disorders and multiple substance use disorders. We also demonstrated that ELAVL2 regulates alternative polyadenylation of NCAM1 and CTNND1, both of which are genes associated with MDD and opioid use disorder.

Conclusion: Our results suggest an important functional role for ELAVL2 in post-transcriptional regulation of genes implicated in psychiatric disorders and antidepressant treatment response.