Medical Student Marmara University School of Medicine Istanbul, Istanbul, Turkey
Background: The Protein Tyrosine Phosphatase Receptor-type D (PTPRD) gene has been linked to substance use disorders (SUDs) by Genome-Wide Association Studies (GWAS). Several SUD GWAS SNP loci near PTRRD map to glucocorticoid receptor (GR) binding sites. Glucocorticoid signaling plays a significant role in SUDs. However, a relationship between PTPRD and GR signaling had not previously been described. Methods: To test whether PTPRD expression might be regulated by GR in central nervous system (CNS) cells, we performed RNA-seq using samples from human induced pluripotent stem cell (hiPSC)-derived astrocytes treated with dexamethasone (DEX). We validated those findings in U251-MG glioblastoma cells with DEX treatment at various concentrations and time points. We also performed RT-qPCR to quantify the expression of 15 PTPRD transcript variants to determine the possible regulation of transcript variants by GR. Results: Two PTPRD SNP loci that were associated with SUD phenotypes mapped to GR binding sites. Furthermore, PTPRD is bound by GR near the SNP loci in a variety of human cell lines based on ENCODE GR ChIP-seq data. We also showed that PTPRD mRNA expression was repressed 20% in hiPSC-derived astrocytes 7 hours after DEX treatment. The extent of PTPRD repression by DEX varied among the 15 PTPRD transcript variants. We identified 4 PTPRD transcript variants in human U251-MG cells for which expression was repressed up to 55% after DEX treatment. Conclusion: PTPRD expression is repressed by GR signaling in hiPSC-derived astrocytes and U251-MG glioblastoma cells, observations that strengthen a possible link between PTPRD transcription and CNS glucocorticoid signaling. Future studies investigating mechanisms of PTPRD SNPs and their relation to glucocorticoid signaling might provide insight into SUD pathogenesis and therapy.
