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Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Convolutional neural network was used to identify an ALS-associated SNP located in the intronic region of <jats:italic>MEF2C<\/jats:italic> (rs304152), residing in a putative enhancer element. To examine the alteration of <jats:italic>MEF2C<\/jats:italic> transcription by the SNP, we generated HEK293T cells carrying the major or minor allele by CRISPR-Cas9. To verify the role of <jats:italic>MEF2C<\/jats:italic>-knockdown (<jats:italic>MEF2C<\/jats:italic>-KD) in mice, we developed AAV expressing shRNA for <jats:italic>MEF2C<\/jats:italic> based on AAV-U6 promoter vector. Neuropathological alterations of <jats:italic>MEF2C<\/jats:italic>-KD mice with mitochondrial dysfunction and motor neuronal damage were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through longitudinal study by tail suspension, inverted grid test and automated gait analysis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Here, we show that enhancer mutation of <jats:italic>MEF2C<\/jats:italic> 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 <jats:italic>MEF2C<\/jats:italic> enhancer decreases expression of mitochondria-encoded genes. Moreover, <jats:italic>MEF2C<\/jats:italic> mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. <jats:italic>MEF2C<\/jats:italic> 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Together, <jats:italic>MEF2C<\/jats:italic> 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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13024-024-00792-y","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T16:58:08Z","timestamp":1738947488000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice"],"prefix":"10.1186","volume":"20","author":[{"given":"Ali","family":"Yousefian-Jazi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyeon","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Hye","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuong Thi Thanh","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uiyeol","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-gyeong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongik","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungeun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Jae","family":"Hyeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyewhon","family":"Rhim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah L.","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grewo","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thor D.","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayeong","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6544-3732","authenticated-orcid":false,"given":"Hoon","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junghee","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"issue":"9","key":"792_CR1","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1016\/j.jmb.2019.02.004","volume":"431","author":"H Haukedal","year":"2019","unstructured":"Haukedal H, Freude K. 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