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Optic atrophy 1 (OPA1), a GTPase at the inner mitochondrial membrane involved in regulating mitochondrial fusion, stability, and energy output, is known to be crucial for neural development: Opa1 heterozygous mice show abnormal brain development, and inactivating mutations in OPA1 are linked to human neurological disorders. Here, we used genetically modified human embryonic and patient-derived induced pluripotent stem cells and reveal that OPA1 haploinsufficiency leads to aberrant nuclear DNA methylation and significantly alters the transcriptional circuitry in neural progenitor cells (NPCs). For instance, expression of the forkhead box G1 transcription factor, which is needed for GABAergic neuronal development, is repressed in OPA1+/- NPCs. Supporting this finding, OPA1+/- NPCs cannot give rise to GABAergic interneurons, whereas formation of glutamatergic neurons is not affected. Taken together, our data reveal that OPA1 controls nuclear DNA methylation and expression of key transcription factors needed for proper neural cell specification. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.


Safak Caglayan, Adnan Hashim, Artur Cieslar-Pobuda, Vidar Jensen, Sidney Behringer, Burcu Talug, Dinh Toi Chu, Christian Pecquet, Marie Rogne, Andreas Brech, Sverre Henning Brorson, Erlend Arnulf Nagelhus, Luciana Hannibal, Antonella Boschi, Kjetil Taskén, Judith Staerk. Optic Atrophy 1 Controls Human Neuronal Development by Preventing Aberrant Nuclear DNA Methylation. iScience. 2020 Jun 26;23(6):101154

PMID: 32450518

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