Transcription Factor MAFF (MAF Basic Leucine Zipper Transcription Factor F) Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism.
Transcription Factor MAFF (MAF Basic Leucine Zipper Transcription Factor F) Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism.
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DOI：
10.1161/circulationaha.120.050186
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发表时间：
2021-05-04
期刊：
影响因子：
37.8
通讯作者：
Schunkert H
中科院分区：
文献类型：
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作者：
von Scheidt M;Zhao Y;de Aguiar Vallim TQ;Che N;Wierer M;Seldin MM;Franzén O;Kurt Z;Pang S;Bongiovanni D;Yamamoto M;Edwards PA;Ruusalepp A;Kovacic JC;Mann M;Björkegren JLM;Lusis AJ;Yang X;Schunkert H
冠状动脉疾病（CAD）是一种多因素疾病，既有遗传原因，也有外源性原因。组织特异性功能网络在动脉粥样硬化发展中的作用尚不清楚。本研究的目的是识别和定位导致动脉粥样硬化的中枢调节因子和网络。基于已知影响小鼠（如敲除模型所示）和人类（如全基因组关联研究（GWAS）所示）动脉粥样硬化风险的数百个基因，对肝脏基因调控网络进行建模。网络中基因的层次顺序和调控方向是基于贝叶斯预测模型以及实验研究，包括染色质免疫沉淀DNA测序（ChIP-Seq），ChIP质谱（ChIP-MS），过表达，小鼠和人肝细胞中的siRNA敲低，以及敲除小鼠实验。使用生物信息学和相关性分析来阐明人类和小鼠中中心基因与CAD表型之间的关联。转录因子MAFF作为肝脏网络的关键驱动因子与CAD GWAS位点的三个人类基因和十一个动脉粥样硬化小鼠基因相互作用。最重要的是，低密度脂蛋白受体（LDLR）基因的表达水平与MAFF在600 CAD患者接受搭桥手术（STARNET）和杂交小鼠多样性面板涉及105个不同的近交系小鼠品系。在非炎症条件下测试MAFF的分子机制，显示MAFF和LDLR在体外和体内之间呈正相关。有趣的是，在LPS刺激（炎症条件）后，观察到体外和体内MAFF和LDLR之间的负相关性。ChIP-MS显示，人CAD GWAS候选物BACH 1在LPS刺激存在下辅助MAFF，其具有在LDLR启动子的MAF识别元件（MARE）处结合的相应异二聚体，以转录下调LDLR表达。转录因子MAFF被鉴定为动脉粥样硬化/CAD相关肝脏网络的新型中央调节因子。MAFF触发了LDLR和其他已知影响CAD风险的基因的背景特异性表达。我们的研究结果表明，MAFF是炎症，脂质和脂蛋白代谢之间的一个缺失环节，也是一个可能的治疗靶点。
Coronary artery disease (CAD) is a multifactorial condition with both genetic and exogenous causes. The contribution of tissue specific functional networks to the development of atherosclerosis remains largely unclear. The aim of this study was to identify and characterise central regulators and networks leading to atherosclerosis. Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knock-out models) and human (as shown by genome-wide association studies (GWAS)) liver gene regulatory networks were modeled. The hierarchical order and regulatory directions of genes within the network were based on Bayesian prediction models as well as experimental studies including chromatin immunoprecipitation DNA-Sequencing (ChIP-Seq), ChIP mass spectrometry (ChIP-MS), overexpression, siRNA knockdown in mouse and human liver cells, and knockout mouse experiments. Bioinformatics and correlation analyses were used to clarify associations between central genes and CAD phenotypes in both human and mouse. The transcription factor MAFF interacted as a key driver of a liver network with three human genes at CAD GWAS loci and eleven atherosclerotic murine genes. Most importantly, expression levels of the low-density lipoprotein receptor (LDLR) gene correlated with MAFF in 600 CAD patients undergoing bypass surgery (STARNET) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested under non-inflammatory conditions showing a positive correlation between MAFF and LDLR in vitro and in vivo. Interestingly, after LPS stimulation (inflammatory conditions) an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. ChIP-MS revealed that the human CAD GWAS candidate BACH1 assists MAFF in the presence of LPS stimulation with respective heterodimers binding at the MAF recognition element (MARE) of the LDLR promoter to transcriptionally downregulate LDLR expression. The transcription factor MAFF was identified as a novel central regulator of an atherosclerosis/CAD relevant liver network. MAFF triggered context specific expression of LDLR and other genes known to affect CAD risk. Our results suggest that MAFF is a missing link between inflammation, lipid and lipoprotein metabolism and a possible treatment target.