Direct targets of MEF2C are enriched for genes associated with schizophrenia and cognitive function and are involved in neuron development and mitochondrial function

IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences
Deema Ali, Aodán Laighneach, Emma Corley, Saahithh Redddi Patlola, Rebecca Mahoney, Laurena Holleran, Declan P. McKernan, John P. Kelly, Aiden P. Corvin, Brian Hallahan, Colm McDonald, Gary Donohoe, Derek W. Morris
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引用次数: 0

Abstract

Myocyte Enhancer Factor 2C (MEF2C) is a transcription factor that plays a crucial role in neurogenesis and synapse development. Genetic studies have identified MEF2C as a gene that influences cognition and risk for neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Here, we investigated the involvement of MEF2C in these phenotypes using human-derived neural stem cells (NSCs) and glutamatergic induced neurons (iNs), which represented early and late neurodevelopmental stages. For these cellular models, MEF2C function had previously been disrupted, either by direct or indirect mutation, and gene expression assayed using RNA-seq. We integrated these RNA-seq data with MEF2C ChIP-seq data to identify dysregulated direct target genes of MEF2C in the NSCs and iNs models. Several MEF2C direct target gene-sets were enriched for SNP-based heritability for intelligence, educational attainment and SCZ, as well as being enriched for genes containing rare de novo mutations reported in ASD and/or developmental disorders. These gene-sets are enriched in both excitatory and inhibitory neurons in the prenatal and adult brain and are involved in a wide range of biological processes including neuron generation, differentiation and development, as well as mitochondrial function and energy production. We observed a trans expression quantitative trait locus (eQTL) effect of a single SNP at MEF2C (rs6893807, which is associated with IQ) on the expression of a target gene, BNIP3L. BNIP3L is a prioritized risk gene from the largest genome-wide association study of SCZ and has a function in mitophagy in mitochondria. Overall, our analysis reveals that either direct or indirect disruption of MEF2C dysregulates sets of genes that contain multiple alleles associated with SCZ risk and cognitive function and implicates neuron development and mitochondrial function in the etiology of these phenotypes.
MEF2C 的直接靶标富含与精神分裂症和认知功能相关的基因,并参与神经元发育和线粒体功能
肌细胞增强因子 2C (MEF2C) 是一种转录因子,在神经发生和突触发育过程中起着至关重要的作用。遗传研究发现,MEF2C 是一个影响认知和神经精神疾病风险的基因,包括自闭症谱系障碍(ASD)和精神分裂症(SCZ)。在此,我们利用代表早期和晚期神经发育阶段的人源神经干细胞(NSCs)和谷氨酸能诱导神经元(iNs)研究了MEF2C参与这些表型的情况。在这些细胞模型中,MEF2C的功能先前已被直接或间接突变破坏,并使用RNA-seq对基因表达进行了检测。我们将这些RNA-seq数据与MEF2C ChIP-seq数据整合在一起,以确定NSCs和iNs模型中MEF2C直接靶基因的失调情况。几个MEF2C直接靶基因组富集于基于SNP的智力、教育程度和SCZ遗传性,并富集于在ASD和/或发育障碍中报告的含有罕见从头突变的基因。这些基因组富集在产前和成年大脑的兴奋性和抑制性神经元中,并参与了广泛的生物过程,包括神经元的生成、分化和发育,以及线粒体功能和能量产生。我们观察到 MEF2C 的一个 SNP(rs6893807,与智商有关)对目标基因 BNIP3L 的表达产生了反式表达量性状位点(eQTL)效应。BNIP3L 是 SCZ 最大的全基因组关联研究中的优先风险基因,在线粒体中具有有丝分裂吞噬功能。总之,我们的分析表明,MEF2C的直接或间接破坏会使包含与SCZ风险和认知功能相关的多个等位基因的基因集失调,并将神经元发育和线粒体功能与这些表型的病因学联系起来。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Genetics
PLoS Genetics 生物-遗传学
CiteScore
8.10
自引率
2.20%
发文量
438
审稿时长
1 months
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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