Global miRNA expression and correlation with mRNA levels in primary human bone cells.
Global miRNA expression and correlation with mRNA levels in primary human bone cells.
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DOI：
10.1261/rna.049148.114
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发表时间：
2015-08
期刊：
影响因子：
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通讯作者：
Kindmark A
中科院分区：
文献类型：
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作者：
Laxman N;Rubin CJ;Mallmin H;Nilsson O;Pastinen T;Grundberg E;Kindmark A
MicroRNAs （miRNAs）是重要的转录后调控因子，最近为我们对基因调控的理解带来了额外的复杂性。本研究的目的是通过评估microrna水平的相关性和个体间变异性，以及microrna和mRNA水平之间的整体相关性，研究可能与骨代谢相关的microrna - mRNA相互作用。这些microrna和mRNA水平是在健康个体骨科手术中获得的一大群人成骨细胞（HOBs）中进行的。我们鉴定了24个mirna的差异表达（DE），并发现9个mirna在男性和女性之间表现出DE。我们发现hsa-miR-29b、hsa-miR-30c2和hsa-miR-125b及其靶基因是骨代谢的重要调节剂。此外，我们使用了全球miRNA-mRNA相关性、mrna表达谱、DE、生物信息学分析和功能研究的综合分析，以确定具有调节成骨细胞分化和细胞外基质生成潜力的mirna的新靶基因。通过过表达和敲低miRNAs的功能研究表明，差异表达的miRNAs hsa-miR-29b、hsa-miR-30c2和hsa-miR-125b靶向与骨代谢高度相关的基因，如胶原、I型、α1 （COL1A1）、骨连接素（SPARC）、矮子相关转录因子2 （RUNX2）、骨钙素（BGLAP）和毛屑相关蛋白（FRZB）。这些mirna通过对靶基因和途径的趋同作用，协调成骨细胞分化和细胞外基质蛋白的关键调节因子的活动，从而控制骨骼基因的表达。
MicroRNAs (miRNAs) are important post-transcriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. The aim of this study was to investigate miRNA–mRNA interactions that may be relevant for bone metabolism by assessing correlations and interindividual variability in miRNA levels as well as global correlations between miRNA and mRNA levels in a large cohort of primary human osteoblasts (HOBs) obtained during orthopedic surgery in otherwise healthy individuals. We identified differential expression (DE) of 24 miRNAs, and found 9 miRNAs exhibiting DE between males and females. We identified hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b and their target genes as important modulators of bone metabolism. Further, we used an integrated analysis of global miRNA–mRNA correlations, mRNA-expression profiling, DE, bioinformatics analysis, and functional studies to identify novel target genes for miRNAs with the potential to regulate osteoblast differentiation and extracellular matrix production. Functional studies by overexpression and knockdown of miRNAs showed that, the differentially expressed miRNAs hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b target genes highly relevant to bone metabolism, e.g., collagen, type I, α1 (COL1A1), osteonectin (SPARC), Runt-related transcription factor 2 (RUNX2), osteocalcin (BGLAP), and frizzled-related protein (FRZB). These miRNAs orchestrate the activities of key regulators of osteoblast differentiation and extracellular matrix proteins by their convergent action on target genes and pathways to control the skeletal gene expression.