Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD <sup>+</sup> and ATP

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Abstract

Background

Aging and neurodegenerative diseases are typical metabolic-related processes. As a metabolism-related long non-coding RNA, EPB41L4A-AS has been reported to be potentially involved in the development of brain aging and neurodegenerative diseases. In this study, we sought to reveal the mechanisms of EPB41L4A-AS in aging and neurodegenerative diseases.

Methods

Human hippocampal gene expression profiles downloaded from the Genotype-Tissue Expression database were analyzed to obtain age-stratified differentially expressed genes; a weighted correlation network analysis algorithm was then used to construct a gene co-expression network of these differentially expressed genes to obtain gene clustering modules. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein–protein interaction network, and correlation analysis were used to reveal the role of EPB41L4A-AS1. The mechanism was verified using Gene Expression Omnibus dataset GSE5281 and biological experiments (construction of cell lines, Real-time quantitative PCR, Western blot, measurement of ATP and NAD ⁺ levels, nicotinamide riboside treatment, Chromatin Immunoprecipitation) in neurons and glial-derived cells.

Results

EPB41L4A-AS1 was downregulated in aging and Alzheimer's disease. EPB41L4A-AS1 related genes were found to be enriched in the electron transport chain and NAD ⁺ synthesis pathway. Furthermore, these genes were highly associated with neurodegenerative diseases and positively correlated with EPB41L4A-AS1. In addition, biological experiments proved that the downregulation of EPB41L4A-AS1 could reduce the expression of these genes via histone H3 lysine 27 acetylation, resulting in decreased NAD ⁺ and ATP levels, while EPB41L4A-AS1 overexpression and nicotinamide riboside treatment could restore the NAD ⁺ and ATP levels.

Conclusions

Downregulation of EPB41L4A-AS1 not only disturbs NAD ⁺ biosynthesis but also affects ATP synthesis. As a result, the high demand for NAD ⁺ and ATP in the brain cannot be met, promoting the development of brain aging and neurodegenerative diseases. However, overexpression of EPB41L4A-AS1 and nicotinamide riboside, a substrate of NAD ⁺ synthesis, can reduce EPB41L4A-AS1 downregulation-mediated decrease of NAD ⁺ and ATP synthesis. Our results provide new perspectives on the mechanisms underlying brain aging and neurodegenerative diseases.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13578-021-00705-2.

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Background Correlation networks are increasingly being used in bioinformatics applications. For example, weighted gene co-expression network analysis is a systems biology method for describing the correlation patterns among genes across microarray samples. Weighted correlation network analysis (WGCNA) can be used for finding clusters (modules) of highly correlated genes, for summarizing such clusters using the module eigengene or an intramodular hub gene, for relating modules to one another and to external sample traits (using eigengene network methodology), and for calculating module membership measures. Correlation networks facilitate network based gene screening methods that can be used to identify candidate biomarkers or therapeutic targets. These methods have been successfully applied in various biological contexts, e.g. cancer, mouse genetics, yeast genetics, and analysis of brain imaging data. While parts of the correlation network methodology have been described in separate publications, there is a need to provide a user-friendly, comprehensive, and consistent software implementation and an accompanying tutorial. Results The WGCNA R software package is a comprehensive collection of R functions for performing various aspects of weighted correlation network analysis. The package includes functions for network construction, module detection, gene selection, calculations of topological properties, data simulation, visualization, and interfacing with external software. Along with the R package we also present R software tutorials. While the methods development was motivated by gene expression data, the underlying data mining approach can be applied to a variety of different settings. Conclusion The WGCNA package provides R functions for weighted correlation network analysis, e.g. co-expression network analysis of gene expression data. The R package along with its source code and additional material are freely available at .

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The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible

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Author and article information

Contributors

Ziqiang Wang: wangziqiang@sdfmu.edu.cn

Yaou Zhang:

ORCID: http://orcid.org/0000-0002-2501-8093

zhangyo@sz.tsinghua.edu.cn

Journal

Journal ID (nlm-ta): Cell Biosci

Journal ID (iso-abbrev): Cell Biosci

Title: Cell & Bioscience

Publisher: BioMed Central (London )

ISSN (Electronic): 2045-3701

Publication date (Electronic): 10 November 2021

Publication date PMC-release: 10 November 2021

Publication date Collection: 2021

Volume: 11

Electronic Location Identifier: 192

Affiliations

[1 ]GRID grid.12527.33, ISNI 0000 0001 0662 3178, Department of Chemical Engineering, , Tsinghua University, ; Beijing, 100084 People’s Republic of China

[2 ]State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055 China

[3 ]GRID grid.12527.33, ISNI 0000 0001 0662 3178, School of Life Sciences, , Tsinghua University, ; Beijing, 100084 China

[4 ]Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055 China

[5 ]GRID grid.12527.33, ISNI 0000 0001 0662 3178, Open FIESTA Center, Tsinghua Shenzhen International Graduate School, , Tsinghua University, ; Shenzhen, 518055 China

[6 ]GRID grid.410587.f, Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, ; Jinan, 250062 China

[7 ]GRID grid.12527.33, ISNI 0000 0001 0662 3178, Department of Biomedical Engineering, , Tsinghua University, ; Beijing, 100084 China

Author information

Yaou Zhang http://orcid.org/0000-0002-2501-8093

Article

Publisher ID: 705

DOI: 10.1186/s13578-021-00705-2

PMC ID: 8579638

PubMed ID: 34758883

SO-VID: 3d9a53a7-d4e7-4f85-a683-f7732b24935b

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 22 September 2021

Date accepted : 30 October 2021

Funding

Funded by: Shenzhen International Cooperation Research Project

Award ID: GJHZ20180929162002061

Award Recipient : Yaou Zhang

Custom metadata

ScienceOpen disciplines: Cell biology

Keywords: aging,neurodegenerative diseases,epb41l4a- as1,nad+,atp,h3k27ac

Data availability:

ScienceOpen disciplines: Cell biology

Keywords: aging, neurodegenerative diseases, epb41l4a- as1, nad+, atp, h3k27ac

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