Loss ofMEF2Cfunction by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice

Ali Yousefian-Jazi, Suhyun Kim, Seung-Hye Choi, Jiyeon Chu, Phuong Thi-Thanh Nguyen, Uiyeol Park, Kayeong Lim, Hongik Hwang, Kyungeun Lee, Yeyun Kim, Seung Jae Hyeon, Hyewhon Rhim, Hannah L. Ryu, Grewo Lim, Thor D. Stein, Hoon Ryu, Junghee Lee
2024 · doi:10.1101/2024.07.15.603186
preprint OA: closed
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The paper investigates how a non-coding, ALS-associated SNP (rs304152) in an intronic putative enhancer of MEF2C affects gene regulation and neuronal mitochondrial function. Using convolutional neural network prediction, CRISPR/Cas9 enhancer editing in cells, and MEF2C deficiency models in upper and lower motor neurons of mice, the authors find that the enhancer mutation reduces MEF2C expression, leading to decreased expression of mitochondria-encoded genes and mitochondrial metabolic disruption characterized by reduced membrane potential and ATP with increased oxidative stress. A key caveat is that the work is framed around ALS mechanisms and enhancer-mediated regulation, so the direct contribution of this specific MEF2C enhancer alteration to broader disease phenotypes beyond motor neurons is not established within the study scope. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Genetic changes and epigenetic modifications are associated with neuronal dysfunction in the pathogenesis of neurodegenerative disorders. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Here, we identified an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element, using convolutional neural network. The enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.
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Abstract Genetic changes and epigenetic modifications are associated with neuronal dysfunction in the pathogenesis of neurodegenerative disorders. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Here, we identified an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element, using convolutional neural network. The enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments. Full Text Availability The license terms selected by the author(s) for this preprint version do not permit archiving in PMC. The full text is available from the preprint server.

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