Transcription Factor MAFF (MAF Basic Leucine Zipper Transcription Factor F) Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism
- 25 February 2021
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American College of Cardiology
- Vol. 143 (18), 1809-1823
- https://doi.org/10.1161/circulationaha.120.050186
Abstract
Background: 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. Methods: 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. Results: 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 LDLRin vitro and in vivo. Interestingly, after LPS stimulation (inflammatory conditions) an inverse correlation between MAFF and LDLRin 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. Conclusions: 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.Keywords
This publication has 81 references indexed in Scilit:
- Large-scale association analysis identifies new risk loci for coronary artery diseaseNature Genetics, 2012
- Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traitsMammalian Genome, 2012
- Systems analysis of eleven rodent disease models reveals an inflammatome signature and key driversMolecular Systems Biology, 2012
- Large-scale association analysis identifies 13 new susceptibility loci for coronary artery diseaseNature Genetics, 2011
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- Plasminogen mediates the atherogenic effects of macrophage-expressed urokinase and accelerates atherosclerosis in apoE-knockout miceProceedings of the National Academy of Sciences of the United States of America, 2008
- Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networksNature Genetics, 2008
- The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-κB target genesProceedings of the National Academy of Sciences of the United States of America, 2007
- Genomewide Association Analysis of Coronary Artery DiseaseThe New England Journal of Medicine, 2007
- Sequence Variations inPCSK9,Low LDL, and Protection against Coronary Heart DiseaseThe New England Journal of Medicine, 2006