Cell-type-specific DNA Methylation Analysis of the Frontal Cortices of Mutant Polg1 Transgenic Mice with Neuronal Accumulation of Deleted Mitochondrial DNA

Overview

Journal Mol Brain

Publisher Biomed Central

Specialties Molecular Biology
Neurology

Date 2022 Jan 7

PMID 34991677

Citations 1

Authors

Hiroko Sugawara

Miki Bundo

Takaoki Kasahara

Yutaka Nakachi

Junko Ueda

Mie Kubota-Sakashita

Kazuya Iwamoto

Tadafumi Kato

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Integrating mitoepigenetics into research in mood disorders: a state-of-the-art review.

Ceylan D, Arat-Celik H, Aksahin I Front Physiol. 2024; 15:1338544.

PMID: 38410811 PMC: 10895490. DOI: 10.3389/fphys.2024.1338544.

References

Longley M, Graziewicz M, Bienstock R, Copeland W . Consequences of mutations in human DNA polymerase gamma. Gene. 2005; 354:125-31. DOI: 10.1016/j.gene.2005.03.029. View

Kasahara T, Takata A, Kato T, Kubota-Sakashita M, Sawada T, Kakita A . Depression-like episodes in mice harboring mtDNA deletions in paraventricular thalamus. Mol Psychiatry. 2015; 21(1):39-48. PMC: 5414076. DOI: 10.1038/mp.2015.156. View

Fries G, Li Q, McAlpin B, Rein T, Walss-Bass C, Soares J . The role of DNA methylation in the pathophysiology and treatment of bipolar disorder. Neurosci Biobehav Rev. 2016; 68:474-488. PMC: 5003658. DOI: 10.1016/j.neubiorev.2016.06.010. View

Allis C, Jenuwein T . The molecular hallmarks of epigenetic control. Nat Rev Genet. 2016; 17(8):487-500. DOI: 10.1038/nrg.2016.59. View

Smits B, Fermont J, Delnooz C, Kalkman J, Bleijenberg G, van Engelen B . Disease impact in chronic progressive external ophthalmoplegia: more than meets the eye. Neuromuscul Disord. 2011; 21(4):272-8. DOI: 10.1016/j.nmd.2010.12.008. View

Nishioka M, Bundo M, Kasai K, Iwamoto K . DNA methylation in schizophrenia: progress and challenges of epigenetic studies. Genome Med. 2012; 4(12):96. PMC: 3580436. DOI: 10.1186/gm397. View

Kasahara T, Ishiwata M, Kakiuchi C, Fuke S, Iwata N, Ozaki N . Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder. Psychiatry Clin Neurosci. 2016; 71(8):518-529. DOI: 10.1111/pcn.12496. View

Petronis A . Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature. 2010; 465(7299):721-7. DOI: 10.1038/nature09230. View

Kasahara T, Kubota M, Miyauchi T, Noda Y, Mouri A, Nabeshima T . Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. Mol Psychiatry. 2006; 11(6):577-93, 523. DOI: 10.1038/sj.mp.4001824. View

10.

Feinberg A . Phenotypic plasticity and the epigenetics of human disease. Nature. 2007; 447(7143):433-40. DOI: 10.1038/nature05919. View

11.

Kubota M, Kasahara T, Iwamoto K, Komori A, Ishiwata M, Miyauchi T . Therapeutic implications of down-regulation of cyclophilin D in bipolar disorder. Int J Neuropsychopharmacol. 2010; 13(10):1355-68. DOI: 10.1017/S1461145710000362. View

12.

Iwamoto K, Bundo M, Ueda J, Oldham M, Ukai W, Hashimoto E . Neurons show distinctive DNA methylation profile and higher interindividual variations compared with non-neurons. Genome Res. 2011; 21(5):688-96. PMC: 3083085. DOI: 10.1101/gr.112755.110. View

13.

Bundo M, Ueda J, Nakachi Y, Kasai K, Kato T, Iwamoto K . Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder. Mol Psychiatry. 2021; 26(7):3407-3418. PMC: 8505249. DOI: 10.1038/s41380-021-01079-0. View

14.

Johnson W, Li W, Meyer C, Gottardo R, Carroll J, Brown M . Model-based analysis of tiling-arrays for ChIP-chip. Proc Natl Acad Sci U S A. 2006; 103(33):12457-62. PMC: 1567901. DOI: 10.1073/pnas.0601180103. View

15.

Mullins N, Forstner A, OConnell K, Coombes B, Coleman J, Qiao Z . Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet. 2021; 53(6):817-829. PMC: 8192451. DOI: 10.1038/s41588-021-00857-4. View