Multi-omic insights into molecular mechanism and therapeutic targets in spinocerebellar ataxia type 7

Soo Hyun Ahn; Yoonhyuk Jang; Bum-Sup Jang; Jangsup Moon; Woo-Jin Lee; Dong-Kyu Park; Jung-Suk Yu; Hyoshin Son; Hyeyoon Kim; Dohyun Han; Heeyoung Seok; Yongmoo Kim; Seo-Yi Shin; Soon-Tae Lee; Kyung-Il Park; Keun-Hwa Jung; Daejong Jeon; Sang Kun Lee; Kon Chu

doi:10.1016/j.omtn.2024.102414

Multi-omic insights into molecular mechanism and therapeutic targets in spinocerebellar ataxia type 7

Mol Ther Nucleic Acids. 2024 Dec 5;36(1):102414. doi: 10.1016/j.omtn.2024.102414. eCollection 2025 Mar 11.

Authors

Soo Hyun Ahn^{1

2}, Yoonhyuk Jang^{1

2

3

4}, Bum-Sup Jang⁵, Jangsup Moon^{1

2

6}, Woo-Jin Lee⁷, Dong-Kyu Park^{2

8}, Jung-Suk Yu^{2

8}, Hyoshin Son⁹, Hyeyoon Kim^{10

11}, Dohyun Han^{10

11}, Heeyoung Seok¹², Yongmoo Kim^{1

2}, Seo-Yi Shin^{1

2}, Soon-Tae Lee^{1

2}, Kyung-Il Park¹³, Keun-Hwa Jung^{1

2}, Daejong Jeon⁸, Sang Kun Lee^{1

2}, Kon Chu^{1

2}

Affiliations

¹ Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
² Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Center for Medical Innovation, Biomedical Research Institute, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea.
³ Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea.
⁴ The National Strategic Technology Research Institute, Seoul 03080, Republic of Korea.
⁵ Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
⁶ Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
⁷ Department of Neurology, Seoul National University Bundang Hospital, Seongnam-si 13620, Republic of Korea.
⁸ Advanced Neural Technologies, Seoul 03087, Republic of Korea.
⁹ Department of Neurology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea.
¹⁰ Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea.
¹¹ Department of Transdisciplinary Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea.
¹² Department of Transdisciplinary Research and Collaboration, Genomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea.
¹³ Department of Neurology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul 06236, Republic of Korea.

Abstract

Recent advances in molecular science have significantly enlightened our mechanistic understanding of spinocerebellar ataxia type 7. To further close remaining gaps, we performed a multi-omics analysis using SCA7^266Q/5Q mice. Entire brain tissue samples were collected from 12-week-old mice, and RNA sequencing, methylation analysis, and proteomic analysis were performed. Results were integrated to identify genes with identical trends in expression across all three analyses. Data from RNA sequencing and methylation analysis revealed 58 significantly hypomethylated-upregulated genes and 62 hypermethylated-downregulated genes, mostly enriched in GO terms of regulation of axonogenesis, channel activity, and monoamine signaling. In the proteomic analysis, 211 upregulated and 281 downregulated DEPs associated mostly with immune response and cellular mobility were identified. Two genes, Fam107b and Tph2, showed differential expressions in both transcriptomic and proteomic analyses. Findings were validated in RT-qPCR as well as open data source analysis. Our study is the first to perform multi-omics analysis in SCA7 mice and will serve as an important reference for future studies.

Keywords: MT: Bioinformatics; molecular targets in SCA7; multi-omics; spinocerebellar ataxia 7.