Dataset Information

Genetic analyses support the contribution of mRNA N⁶-methyladenosine (m⁶A) modification to human disease heritability.

ABSTRACT: N⁶-methyladenosine (m⁶A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m⁶A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m⁶A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m⁶A QTLs are largely independent of expression and splicing QTLs and are enriched with binding sites of RNA-binding proteins, RNA structure-changing variants and transcriptional features. Joint analysis of the QTLs of m⁶A and related molecular traits suggests that the downstream effects of m⁶A are heterogeneous and context dependent. We identified proteins that mediate m⁶A effects on translation. Through integration with data from genome-wide association studies, we show that m⁶A QTLs contribute to the heritability of various immune and blood-related traits at levels comparable to splicing QTLs and roughly half of expression QTLs. By leveraging m⁶A QTLs in a transcriptome-wide association study framework, we identified putative risk genes of these traits.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7483307 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Genetic analyses support the contribution of mRNA N6-methyladenosine (m6A) modification to human disease heritability.

Zhang Zijie Z Luo Kaixuan K Zou Zhongyu Z Qiu Maguanyun M Tian Jiakun J Sieh Laura L Shi Hailing H Zou Yuxin Y Wang Gao G Morrison Jean J Zhu Allen C AC Qiao Min M Li Zhongshan Z Stephens Matthew M He Xin X He Chuan C

Nature genetics 20200629 9

N6-methyladenosine (m6A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m6A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m6A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m6A QTLs are largely independent of expression and splicing QTLs and are enriched wit ...[more]

PMID: 32601472

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Project description:N1-Methyladenosine (m1A) is an abundant modification of transcripts, plays important roles in regulating mRNA structure and translation efficiency, and is dynamically regulated under stress. However, the characteristics and functions of mRNA m1A modification in primary neurons and oxygen glucose deprivation/reoxygenation (OGD/R) induced remain unclear. We first constructed a mouse cortical neuron OGD/R model and then used methylated RNA immunoprecipitation (MeRIP) and sequencing technology to demonstrate that m1A modification is abundant in neuron mRNAs and dynamically regulated during OGD/R induction. Our study suggests that Trmt10c, Alkbh3, and Ythdf3 may be m1A-regulating enzymes in neurons during OGD/R induction. The level and pattern of m1A modification change significantly during OGD/R induction, and differential methylation is closely associated with the nervous system. Our findings show that m1A peaks in cortical neurons aggregate at both the 5' and 3' untranslated regions. m1A modification can regulate gene expression, and peaks in different regions have different effects on gene expression. By analysing m1A-seq and RNA-seq data, we show a positive correlation between differentially methylated m1A peaks and gene expression. The correlation was verified by using qRT-PCR and MeRIP-RT-PCR. Moreover, we selected human tissue samples from Parkinson's disease (PD) and Alzheimer's disease (AD) patients from the Gene Expression Comprehensive (GEO) database to analyse the selected differentially expressed genes (DEGs) and differential methylation modification regulatory enzymes, respectively, and found similar differential expression results. We highlight the potential relationship between m1A modification and neuronal apoptosis following OGD/R induction. Furthermore, by mapping mouse cortical neurons and OGD/R-induced modification characteristics, we reveal the important role of m1A modification in OGD/R and gene expression regulation, providing new ideas for research on neurological damage.

Dataset Information

Genetic analyses support the contribution of mRNA N⁶-methyladenosine (m⁶A) modification to human disease heritability.

Publications

Genetic analyses support the contribution of mRNA N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification to human disease heritability.

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