24RNA-SEQ analysis in hiPSC-derived neurons from patients with schizophrenia

Stertz, Laura; Pei, Guangsheng; Jia, Peilin; Li, Shenglan; Raventós Vorst, Henriette; Liu, Ying; Zhao, Zhongming; Walss Bass, Consuelo

24RNA-SEQ analysis in hiPSC-derived neurons from patients with schizophrenia

Fecha

2019-07-26

Tipo

actas de congreso

Autores

Stertz, Laura

Pei, Guangsheng

Jia, Peilin

Li, Shenglan

Raventós Vorst, Henriette

Liu, Ying

Zhao, Zhongming

Walss Bass, Consuelo

Resumen

Background: Human induced pluripotent stem cells (hiPSC) have provided a new way of studying schizophrenia (SZ), by allowing the establishment of brain cellular models accounting for the patient genetic background. Here we conducted an exploratory RNA-sequencing profiling study of cell lines derived from hiPSCs generated from lymphoblastoid cell lines (LCL) of subjects from the population isolate of the Central Valley of Costa Rica (CVCR). Methods: Five cell lines (LCL, hiPSC, NPC, cortical neurons and astrocytes) derived from 6 healthy controls and 7 SZ patients from the CVCR were generated using standard methodology. RNA from these cells was sequenced using Illumina HiSeqTM2500. Normalization and differential expression (DE) analysis were performed using DESeq2 (|FC| > 1.5 e BH corrected p-value < 0.05). Functional enrichment analysis was performed using DAVID 6.8. Results: hiPSC-derived neurons were responsible for 94.4% of the variance seen on DE analyses. We found 454 genes differently expressed on neurons differentiated from SZ compared to HC. Noteworthy, one of these genes was ZNF804A (FDR = 0.032), a strong candidate gene for schizophrenia susceptibility, with solid evidence of association from GWAS. Discussion: ZNF804A is a zinc finger protein has been shown to regulate neurite outgrowth, dendritic spine maintenance and activity-dependent structural plasticity. It is expressed broadly throughout the brain, especially in the developing hippocampus and the cortex, as well as in the adult cerebellum. A great advantage of using iPS-derived cells is that the effect of outside environmental influences, such as use of medications, is removed and only the effects of genetic composition, which is unchanged by transformation, are left. The DE of ZNF804A only on hiPSC-neurons highlight the crucial role that this protein can have on SZ pathology during neuronal development. Functional studies will help us further characterize this mechanism.