Research Paper Volume 13, Issue 3 pp 3680—3698
Polyglutamine-expanded ataxin3 alter specific gene expressions through changing DNA methylation status in SCA3/MJD
- 1 Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
- 2 State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, P.R. China
- 3 Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, P.R. China
- 4 National Clinical Research Center for Geriatric Diseases, Changsha, Hunan, P. R. China
- 5 School of Information Science and Engineering, Central South University, Changsha, China
Received: June 19, 2020 Accepted: October 27, 2020 Published: December 19, 2020
https://doi.org/10.18632/aging.202331How to Cite
Copyright: © 2020 Ding et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
DNA methylation has recently been linked to transcriptional dysregulation and neuronal dysfunction in polyglutamine (polyQ) disease. This study aims to determine whether (CAG)n expansion in ATXN3 perturbs DNA methylation status and affects gene expression. We analyzed DNA methylation throughout the genome using reduced representation bisulfite sequencing (RRBS) and confirmed the results using MethylTarget sequencing. Dynamic changes in DNA methylation, transcriptional and translational levels of specific genes were detected using BSP, qRT-PCR and western blot. In total, 135 differentially methylated regions (DMRs) were identified between SCA3/MJD and WT mouse cerebellum. KEGG analysis revealed differentially methylated genes involved in amino acid metabolism, Hedgehog signaling pathway, thyroid cancer, tumorigenesis and other pathways. We focused on DMRs that were directly associated with gene expression. On this basis, we further assessed 7 genes, including 13 DMRs, for DNA methylation validation and gene expression. We found that the methylation status of the DMRs of En1 and Nkx2-1 was negatively associated with their transcriptional and translational levels and that alteration of the DNA methylation status of DMRs and the corresponding transcription occurred before dyskinesia in SCA3/MJD mice. These results revealed novel DNA methylation-regulated genes, En1 and Nkx2-1, which may be useful for understanding the pathogenesis of SCA3/MJD.