Optic Atrophy 1 Controls Human Neuronal Development by Preventing Aberrant Nuclear DNA Methylation

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

doi:10.1016/j.isci.2020.101154

Optic Atrophy 1 Controls Human Neuronal Development by Preventing Aberrant Nuclear DNA Methylation

iScience. 2020 Jun 26;23(6):101154. doi: 10.1016/j.isci.2020.101154. Epub 2020 May 11.

Authors

Safak Caglayan¹, Adnan Hashim¹, Artur Cieslar-Pobuda¹, Vidar Jensen², Sidney Behringer³, Burcu Talug¹, Dinh Toi Chu¹, Christian Pecquet⁴, Marie Rogne¹, Andreas Brech⁵, Sverre Henning Brorson⁶, Erlend Arnulf Nagelhus², Luciana Hannibal³, Antonella Boschi⁷, Kjetil Taskén⁸, Judith Staerk⁹

Affiliations

¹ Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, 0318 Oslo, Norway.
² GliaLab and Letten Centre, Division of Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
³ Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Mathildenstraße 1, 79106 Freiburg, Germany.
⁴ Ludwig Institute for Cancer Research Brussels, 1200 Brussels, Belgium; Université Catholique de Louvain and de Duve Institute, 1200 Brussels, Belgium.
⁵ Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.
⁶ Department of Pathology, Oslo University Hospital, 0424 Oslo, Norway.
⁷ Department of Ophthalmology, Cliniques Universitaires Saint-Luc, UCL, 1200 Brussels, Belgium.
⁸ Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, 0318 Oslo, Norway; Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
⁹ Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, 0318 Oslo, Norway; Department of Haematology, Oslo University Hospital, 0424 Oslo, Norway. Electronic address: judith.staerk@ncmm.uio.no.

Abstract

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.

Keywords: Developmental Neuroscience; Neurogenetics.