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

被引：29

作者：

Caglayan, Safak ^{[1
,2
]}

Hashim, Adnan ^{[1
,2
]}

Cieslar-Pobuda, Artur ^{[1
,2
]}

Jensen, Vidar ^{[3
,4
]}

Behringer, Sidney ^{[5
]}

Talug, Burcu ^{[1
,2
]}

Dinh Toi Chu ^{[1
,2
]}

Pecquet, Christian ^{[6
,7
]}

Rogne, Marie ^{[1
,2
]}

Brech, Andreas ^{[8
]}

Brorson, Sverre Henning ^{[9
]}

Nagelhus, Erlend Arnulf ^{[3
,4
]}

Hannibal, Luciana ^{[5
]}

Boschi, Antonella ^{[10
]}

Tasken, Kjetil ^{[1
,2
,11
,12
]}

Staerk, Judith ^{[1
,2
,13
,14
]}

机构：

[1] Univ Oslo, Ctr Mol Med Norway, Nord EMBL Partnership, N-0318 Oslo, Norway

[2] Oslo Univ Hosp, N-0318 Oslo, Norway

[3] Univ Oslo, GliaLab, Div Physiol, Dept Mol Med,Inst Basic Med Sci, N-0317 Oslo, Norway

[4] Univ Oslo, Letten Ctr, Div Physiol, Dept Mol Med,Inst Basic Med Sci, N-0317 Oslo, Norway

[5] Univ Freiburg, Dept Gen Pediat Adolescent Med & Neonatol, Fac Med, Lab Clin Biochem & Metab,Med Ctr, Mathildenstr 1, D-79106 Freiburg, Germany

[6] Ludwig Inst Canc Res Brussels, B-1200 Brussels, Belgium

[7] Catholic Univ Louvain, B-1200 Brussels, Belgium

[8] de Duve Inst, B-1200 Brussels, Belgium

[9] Oslo Univ Hosp, Inst Canc Res, Dept Mol Cell Biol, N-0424 Oslo, Norway

[10] Oslo Univ Hosp, Dept Pathol, N-0424 Oslo, Norway

[11] UCL, Clin Univ St Luc, Dept Ophthalmol, B-1200 Brussels, Belgium

[12] Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, N-0424 Oslo, Norway

[13] Univ Oslo, Inst Clin Med, N-0318 Oslo, Norway

[14] Oslo Univ Hosp, Dept Haematol, N-0424 Oslo, Norway

来源：

ISCIENCE | 2020年 / 23卷 / 06期

关键词：

MITOCHONDRIAL MORPHOLOGY; BASAL FOREBRAIN; STEM-CELLS; OPA1; DIFFERENTIATION; GENE; EXPRESSION; EPIGENETICS; TRANSCRIPT; INHIBITION;

D O I：

10.1016/j.isci.2020.101154

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：40

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