Centre for Neuroimaging, Cognition and Genomics (NICOG), University of Galway, Ireland.
School of Biological and Chemical Sciences, University of Galway, Ireland.
PLoS Genet. 2024 Sep 11;20(9):e1011093. doi: 10.1371/journal.pgen.1011093. eCollection 2024 Sep.
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.
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中起着至关重要的作用。遗传研究表明，MEF2C 是影响认知和神经精神障碍风险的基因，包括自闭症谱系障碍（ASD）和精神分裂症（SCZ）。在这里，我们使用人类来源的神经干细胞（NSCs）和谷氨酸能诱导神经元（iNs）研究了 MEF2C 在这些表型中的作用，这些细胞模型代表了早期和晚期神经发育阶段。对于这些细胞模型，MEF2C 功能以前已经通过直接或间接突变被破坏，并使用 RNA-seq 测定基因表达。我们将这些 RNA-seq 数据与 MEF2C ChIP-seq 数据整合，以鉴定 NSCs 和 iNs 模型中 MEF2C 失调的直接靶基因。几个 MEF2C 直接靶基因集富集了基于 SNP 的智力、教育程度和 SCZ 的遗传力，以及包含 ASD 和/或发育障碍中报道的罕见新生突变的基因。这些基因集在产前和成年大脑的兴奋性和抑制性神经元中均富集，并参与广泛的生物学过程，包括神经元生成、分化和发育以及线粒体功能和能量产生。我们观察到 MEF2C 上的单个 SNP（rs6893807，与 IQ 相关）对靶基因 BNIP3L 表达的跨表达数量性状基因座（eQTL）效应。BNIP3L 是 SCZ 最大全基因组关联研究中优先考虑的风险基因，并且在线粒体中具有自噬作用。总的来说，我们的分析表明，MEF2C 的直接或间接破坏会扰乱包含多个与 SCZ 风险和认知功能相关的等位基因的基因集，并暗示神经元发育和线粒体功能与这些表型的病因有关。
