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The Landscape of m6A Regulators in Multiple Brain Regions of Alzheimer’s Disease

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Abstract

Alzheimer’s disease research has been conducted for many years, yet no effective cure methods have been found. N6-methyladenosine (m6A) RNA methylation, an essential post-transcriptional regulation mechanism, has been discovered to affect essential neurobiological processes, such as brain cell development and aging, which are closely related to neurodegenerative diseases such as Alzheimer’s disease. The relationship between Alzheimer’s disease and the m6A mechanism still needs further investigation. Our work evaluated the alteration profile of m6A regulators and their influences on Alzheimer’s disease in 4 brain regions: the postcentral gyrus, superior frontal gyrus, hippocampus, and entorhinal cortex. We found that the expression levels of the m6A regulators FTO, ELAVL1, and YTHDF2 were altered in Alzheimer’s disease and were related to pathological development and cognitive levels. We also assessed AD-related biological processes influenced by m6A regulators via GSEA and GSVA method. Biological Processes Gene Ontology terms including memory, cognition, and synapse-signaling were found to potentially be affected by m6A regulators in AD. We also found different m6A modification patterns in AD samples among different brain regions, mainly due to differences in m6A readers. Finally, we further evaluated the importance of AD-related regulators based on the WGCNA method, assessed their potential targets based on correlation relationships, and constructed diagnostic models in 3 of all 4 regions using hub regulators, including FTO, YTHDC1, YTHDC2, etc., and their potential targets. This work aims to provide a reference for the follow-up study of m6A and Alzheimer’s disease.

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Funding

This work was supported in part by grants from the National Natural Science Foundation of China (81701078), the Natural Science Foundation of Heilongjiang Province of China (Outstanding Youth Foundation,YQ2022H003), the University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province (UNPYSCT-2016190), China Postdoctoral Science Foundation (2016M600261, 2018T110317), Heilongjiang Postdoctoral Financial Assistance (LBH-Z15163), the Innovative Science Research Project of Harbin Medical University (2016JCZX37), and Heilongjiang Touyan Innovation Team Program.

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  1. Zi Jie Liu and Qing **a contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Harbin Medical University, No. 157 Harbin health care road, Nangang District, Harbin, China

    ZiJie Liu, Qing **a, Xue Zhao, FeiFei Zheng, JiaYing **ao, FangLiang Ge, DaYong Wang & Xu Gao

  2. Dongzhimen Hospital, Bei**g University of Chinese Medicine, Bei**g, China

    Qing **a

  3. Basic Medical Institute, Heilongjiang Medical Science Academy, No. 157 Harbin health care road, Nangang District, Harbin, China

    DaYong Wang & Xu Gao

  4. Translational Medicine Center of Northern China, No. 157 Harbin health care road, Nangang District, Harbin, China

    DaYong Wang & Xu Gao

  5. Key Laboratory of Heilongjiang Province for Genetically Modified Animals, No. 157 Harbin health care road, Nangang District, Harbin, China

    DaYong Wang & Xu Gao

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  1. ZiJie Liu
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Contributions

All authors contributed to the article. YongDa Wang and Xu Gao had the idea for the article. The first draft of the manuscript was written by Qing **a and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Supplementary information

ESM 1

Supplementary Fig. 1 Threshold picking for WGCNA network construction among four brain regions. (A) R^2 and mean connectivity for different beta of the WCGNA network in the PG region, (B) the SFG region, (C) the HP region, (D) and the EC region. (PNG 255 kb)

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Supplementary Fig. 2 Biological processes related to AD. (A) Venn graph of biological processes differences in activities among four brain regions. (B) GSEA results of significant GO: BP terms in all 4 brain regions. (C) Relationships between key biological processes and AD-related regulators in the PG region, (D) the SFG region, (E) the HP region, (F) and the EC region. (PNG 742 kb)

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Supplementary Fig. 3 Identification of different modification patterns in AD samples among four brain regions. (A) Heatmaps of consensus clustering results in the PG region, (B) the SFG region, (C) the HP region, (D) and the EC region. (PNG 101 kb)

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Supplementary Fig.4 Relationships of key regulators with modules and phenotypes. (A) Gene significance of regulators to phenotypes (GS > 0.2 shown) in the PG region, (B) the SFG region, (C) the HP region, (D) and the EC region. (E) Module membership of key regulators to modules (|MM| > 0.65 shown) in the PG region, (F) the SFG region, (G) the HP region, (H) and the EC region. (PNG 297 kb)

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ESM 5

Supplementary Fig. 5 Hub genes potentially regulated by m6A regulators in the SFG region and the HP region. (A) Results of the assessment of regulatory evidence between FTO, (B) RBM15B and target genes in the SFG region and (C) YTHDC1 in the EC region. The bars represent (from right to left) correlation with the corresponding regulator, gene name, evidence of change after perturbation of regulator, evidence of interaction between regulator and gene transcript, and evidence of m6A or m6Am modification on gene transcript. Genes that show evidence of changes after regulator perturbation and interaction with the corresponding regulator are shown in the SFG region. Genes that show evidence of changes after regulator perturbation are shown in the HP region. Colors represent the relation between target genes and AD. (PNG 628 kb)

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ESM 6

Supplementary Fig. 6 Hub genes potentially regulated by m6A regulators in the EC and HP regions. (A) Results of the assessment of regulatory evidence between the target gene YTHDC2 in the EC region and (B) YTHDC1 in the HP region. The bars represent (from right to left) correlation with the corresponding regulator, gene name, evidence of change after perturbation of regulator, evidence of interaction between regulator and gene transcript, and evidence of m6A or m6Am modification on gene transcript. Genes that show evidence of changes after regulator perturbation and interaction with the corresponding regulator are shown in the EC region. Genes that show evidence of changes after regulator perturbation are shown in the HP region. Colors represent relations between target genes and AD. (PNG 1592 kb)

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ESM 7

Supplementary Fig. 7 Hub genes potentially regulated by m6A regulators in the HP region. (A) Results of the assessment of regulatory evidence between the target genes FTO and (B) YTHDF2 in the HP region. The bars represent (from right to left) correlation with the corresponding regulator, gene name, evidence of change after perturbation of regulator, evidence of interaction between regulator and gene transcript, and evidence of m6A or m6Am modification on gene transcript. Genes that show evidence of changes after regulator perturbation are shown in the HP region. Colors represent the relation between target genes and AD. (PNG 2849 kb)

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Liu, Z., **a, Q., Zhao, X. et al. The Landscape of m6A Regulators in Multiple Brain Regions of Alzheimer’s Disease. Mol Neurobiol 60, 5184–5198 (2023). https://doi.org/10.1007/s12035-023-03409-5

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  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03409-5

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