Functional characterization of the schizophrenia associated gene AS3MT identifies a role in neuronal development

IF 1.6 3区 医学 Q3 GENETICS & HEREDITY
Sam J. Washer, Robert Flynn, Asami Oguro-Ando, Eilis Hannon, Joe Burrage, Aaron Jeffries, Jonathan Mill, Emma L. Dempster
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引用次数: 1

Abstract

Genome-wide association studies (GWAS) have identified multiple genomic regions associated with schizophrenia, although many variants reside in noncoding regions characterized by high linkage disequilibrium (LD) making the elucidation of molecular mechanisms challenging. A genomic region on chromosome 10q24 has been consistently associated with schizophrenia with risk attributed to the AS3MT gene. Although AS3MT is hypothesized to play a role in neuronal development and differentiation, work to fully understand the function of this gene has been limited. In this study we explored the function of AS3MT using a neuronal cell line (SH-SY5Y). We confirm previous findings of isoform specific expression of AS3MT during SH-SY5Y differentiation toward neuronal fates. Using CRISPR-Cas9 gene editing we generated AS3MT knockout SH-SY5Y cell lines and used RNA-seq to identify significant changes in gene expression in pathways associated with neuronal development, inflammation, extracellular matrix formation, and RNA processing, including dysregulation of other genes strongly implicated in schizophrenia. We did not observe any morphological changes in cell size and neurite length following neuronal differentiation and MAP2 immunocytochemistry. These results provide novel insights into the potential role of AS3MT in brain development and identify pathways through which genetic variation in this region may confer risk for schizophrenia.

Abstract Image

精神分裂症相关基因AS3MT的功能表征确定了神经元发育中的作用
全基因组关联研究(GWAS)已经确定了与精神分裂症相关的多个基因组区域,尽管许多变异存在于以高连锁不平衡(LD)为特征的非编码区域,这使得分子机制的阐明具有挑战性。染色体10q24上的基因组区域一直与精神分裂症相关,其风险归因于AS3MT基因。尽管AS3MT被假设在神经元发育和分化中发挥作用,但充分了解该基因功能的工作仍然有限。在这项研究中,我们利用一种神经细胞系(SH-SY5Y)来探索AS3MT的功能。我们证实了先前在SH-SY5Y向神经元命运分化过程中AS3MT异构体特异性表达的发现。使用CRISPR-Cas9基因编辑,我们生成了AS3MT敲除SH-SY5Y细胞系,并使用RNA-seq鉴定了与神经元发育、炎症、细胞外基质形成和RNA加工相关的通路中基因表达的显著变化,包括与精神分裂症密切相关的其他基因的失调。我们没有观察到神经元分化和MAP2免疫细胞化学后细胞大小和神经突长度的任何形态学变化。这些结果为AS3MT在大脑发育中的潜在作用提供了新的见解,并确定了该区域遗传变异可能导致精神分裂症风险的途径。
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来源期刊
CiteScore
5.90
自引率
7.10%
发文量
40
审稿时长
4-8 weeks
期刊介绍: Neuropsychiatric Genetics, Part B of the American Journal of Medical Genetics (AJMG) , provides a forum for experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. It is a resource for novel genetics studies of the heritable nature of psychiatric and other nervous system disorders, characterized at the molecular, cellular or behavior levels. Neuropsychiatric Genetics publishes eight times per year.
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