Path from schizophrenia genomics to biology: gene regulation and perturbation in neurons derived from induced pluripotent stem cells and genome editing

Abstract

Schizophrenia (SZ) is a devastating mental disorder afflicting 1% of the population. Recent genome-wide association studies (GWASs) of SZ have identified >100 risk loci. However, the causal variants/genes and the causal mechanisms remain largely unknown, which hinders the translation of GWAS findings into disease biology and drug targets. Most risk variants are noncoding, thus likely regulate gene expression. A major mechanism of transcriptional regulation is chromatin remodeling, and open chromatin is a versatile predictor of regulatory sequences. MicroRNA-mediated post-transcriptional regulation plays an important role in SZ pathogenesis. Neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs) provide an experimental model to characterize the genetic perturbation of regulatory variants that are often specific to cell type and/or developmental stage. The emerging genome-editing technology enables the creation of isogenic iPSCs and neurons to efficiently characterize the effects of SZ-associated regulatory variants on SZ-relevant molecular and cellular phenotypes involving dopaminergic, glutamatergic, and GABAergic neurotransmissions. SZ GWAS findings equipped with the emerging functional genomics approaches provide an unprecedented opportunity for understanding new disease biology and identifying novel drug targets.

Concise Review: Progress and Challenges in Using Human Stem Cells for Biological and Therapeutics Discovery: Neuropsychiatric Disorders

“…A substantial proportion of common variation associated with neuropsychiatric disorder risk is in noncoding regulatory regions of the genome, as was demonstrated for SCZ . Thus, a logical next step is to perform transcriptomic and open chromatin analysis on patient post‐mortem tissue and patient‐derived hiPSCs as a means to identify the causal variants and global unbiased case‐control differences in gene expression . An important caveat to this approach is the still rudimentary state of most cell differentiation protocols, as important functional genomic signal could be lost in heterogeneous tissue or cultures, while spurious artifacts could be generated from hiPSC derivatives that are not adequately optimized.…”

Are reprogrammed cells a useful tool for studying dopamine dysfunction in psychotic disorders? A review of the current evidence

“…There is a limited number of loci of relatively high impact such as Disrupted in schizophrenia 1 (DISC1), first characterized as a risk factor in a Scottish family (Millar et al ., ), or the deletion 22q11.2, which causes the DiGeorge syndrome (Lindsay et al ., ). A vast number of low impact risk loci have been identified over time, each contributing only marginally to the manifestation of the disorder in an individual (Duan, ). Yet, a significant proportion of heritability found in twin studies remains unaccounted for (Manolio et al ., ; Eichler et al ., ).…”

“…Meir Jacobs’ review from 2015 gives an overview about possibilities and limitations of iPSC‐based studies in the field of SCZ (Jacobs, ). A technical review is provided by Duan, ().…”

miR-137 and miR-491 Negatively Regulate Dopamine Transporter Expression and Function in Neural Cells

“…They regulate *30% of the DNA in the genome [18] and can regulate gene expression at many levels, including the transcriptional, post-transcriptional, translational, and epigenetic levels, thus participating in the evolution of a species, embryonic development, metabolism, and the occurrence of disease [18,19]. The roles of miRNAs in the nervous system have been studied extensively, from physiology to pathology [20,21]. Most seed regions of miRNAs are located in the 3 0 UTR of the gene's mRNA, and miRNAs may regulate the post-transcriptional level of DATs through the 3 0 UTR of SLC6A3 mRNA.…”