Cell-type-specific DNA methylation analysis of the frontal cortices of mutant Polg1 transgenic mice with neuronal accumulation of deleted mitochondrial DNA

Molecular Brain

Takaoki Kasahara¹  Miki Bundo²  Yutaka Nakachi²  Kazuya Iwamoto²  Junko Ueda²  Mie Kubota-Sakashita³  Tadafumi Kato³  Hiroko Sugawara⁴ 

[1] Career Development Program, RIKEN Center for Brain Science, Saitama, Japan;Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, 860-8556, Kumamoto-shi, Kumamoto, Japan;Department of Psychiatry and Behavior Science, Graduate School of Medicine, Juntendo University, 3-1-3 Hongo, Bunkyo-ku, 113-8431, Tokyo, Japan;Department of Psychiatry, Kansai Rosai Hospital, Amagasaki, Japan;Department of Psychiatry, Graduate School of Medicine, Osaka University, Osaka, Japan;

关键词: Bipolar disorder;    Schizophrenia;    DNA methylation;    Neuron;    Nonneuron;    Mitochondrial dysfunction;   

DOI  :  10.1186/s13041-021-00894-4

来源: Springer

【 摘 要 】

Bipolar disorder (BD) is a severe psychiatric disorder characterized by repeated conflicting manic and depressive states. In addition to genetic factors, complex gene–environment interactions, which alter the epigenetic status in the brain, contribute to the etiology and pathophysiology of BD. Here, we performed a promoter-wide DNA methylation analysis of neurons and nonneurons derived from the frontal cortices of mutant Polg1 transgenic (n = 6) and wild-type mice (n = 6). The mutant mice expressed a proofreading-deficient mitochondrial DNA (mtDNA) polymerase under the neuron-specific CamK2a promoter and showed BD-like behavioral abnormalities, such as activity changes and altered circadian rhythms. We identified a total of 469 differentially methylated regions (DMRs), consisting of 267 neuronal and 202 nonneuronal DMRs. Gene ontology analysis of DMR-associated genes showed that cell cycle-, cell division-, and inhibition of peptide activity-related genes were enriched in neurons, whereas synapse- and GABA-related genes were enriched in nonneurons. Among the DMR-associated genes, Trim2 and Lrpprc showed an inverse relationship between DNA methylation and gene expression status. In addition, we observed that mutant Polg1 transgenic mice shared several features of DNA methylation changes in postmortem brains of patients with BD, such as dominant hypomethylation changes in neurons, which include hypomethylation of the molecular motor gene and altered DNA methylation of synapse-related genes in nonneurons. Taken together, the DMRs identified in this study will contribute to understanding the pathophysiology of BD from an epigenetic perspective.

【 授权许可】

CC BY