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Genome-wide pQTL analysis of protein expression regulatory networks in the human liver.

ABSTRACT: BACKGROUND:Previous expression quantitative trait loci (eQTL) studies have identified thousands of genetic variants to be associated with gene expression at the mRNA level in the human liver. However, protein expression often correlates poorly with mRNA levels. Thus, protein quantitative trait loci (pQTL) study is required to identify genetic variants that regulate protein expression in human livers. RESULTS:We conducted a genome-wide pQTL study in 287 normal human liver samples and identified 900 local pQTL variants and 4026 distant pQTL variants. We further discovered 53 genome hotspots of pQTL variants. Transcriptional region mapping analysis showed that 1133 pQTL variants are in transcriptional regulatory regions. Genomic region enrichment analysis of the identified pQTL variants revealed 804 potential regulatory interactions among 595 predicted regulators (e.g., non-coding RNAs) and 394 proteins. Moreover, pQTL variants and trait-variant integration analysis implied several novel mechanisms underlying the relationships between protein expression and liver diseases, such as alcohol dependence. Notably, over 2000 of the identified pQTL variants have not been reported in previous eQTL studies, suggesting extensive involvement of genetic polymorphisms in post-transcriptional regulation of protein expression in human livers. CONCLUSIONS:We have partially established protein expression regulation networks in human livers and generated a wealth of pQTL data that could serve as a valuable resource for the scientific community.

SUBMITTER: He B

PROVIDER: S-EPMC7418398 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Genome-wide pQTL analysis of protein expression regulatory networks in the human liver.

He Bing B Shi Jian J Wang Xinwen X Jiang Hui H Zhu Hao-Jie HJ

BMC biology 20200810 1

<h4>Background</h4>Previous expression quantitative trait loci (eQTL) studies have identified thousands of genetic variants to be associated with gene expression at the mRNA level in the human liver. However, protein expression often correlates poorly with mRNA levels. Thus, protein quantitative trait loci (pQTL) study is required to identify genetic variants that regulate protein expression in human livers.<h4>Results</h4>We conducted a genome-wide pQTL study in 287 normal human liver samples a ...[more]

PMID: 32778093

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Project description:Despite recent advances in cancer management, colorectal cancer (CRC) remains the third most common cancer and a major health-care problem worldwide. MicroRNAs have recently emerged as key regulators of cancer development and progression by targeting multiple cancer-related genes; however, such regulatory networks are not well characterized in CRC. Thus, the aim of this study was to perform global messenger RNA (mRNA) and microRNA expression profiling in the same CRC samples and adjacent normal tissues and to identify potential miRNA-mRNA regulatory networks. Our data revealed 1273 significantly upregulated and 1902 downregulated genes in CRC. Pathway analysis revealed significant enrichment in cell cycle, integrated cancer, Wnt (wingless-type MMTV integration site family member), matrix metalloproteinase, and TGF-β pathways in CRC. Pharmacological inhibition of Wnt (using XAV939 or IWP-2) or TGF-β (using SB-431542) pathways led to dose- and time-dependent inhibition of CRC cell growth. Similarly, our data revealed up- (42) and downregulated (61) microRNAs in the same matched samples. Using target prediction and bioinformatics, ~77% of the upregulated genes were predicted to be targeted by microRNAs found to be downregulated in CRC. We subsequently focused on EZH2 (enhancer of zeste homolog 2 ), which was found to be regulated by hsa-miR-26a-5p and several members of the let-7 (lethal-7) family in CRC. Significant inverse correlation between EZH2 and hsa-miR-26a-5p (R(2)=0.56, P=0.0001) and hsa-let-7b-5p (R(2)=0.19, P=0.02) expression was observed in the same samples, corroborating the belief of EZH2 being a bona fide target for these two miRNAs in CRC. Pharmacological inhibition of EZH2 led to significant reduction in trimethylated histone H3 on lysine 27 (H3K27) methylation, marked reduction in cell proliferation, and migration in vitro. Concordantly, small interfering RNA-mediated knockdown of EZH2 led to similar effects on CRC cell growth in vitro. Therefore, our data have revealed several hundred potential miRNA-mRNA regulatory networks in CRC and suggest targeting relevant networks as potential therapeutic strategy for CRC.

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Genome-wide pQTL analysis of protein expression regulatory networks in the human liver.

Publications

Genome-wide pQTL analysis of protein expression regulatory networks in the human liver.

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