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  Transcription Factor MAFF (MAF Basic Leucine Zipper Transcription Factor F) Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism

von Scheidt, M., Zhao, Y., de Aguiar Vallim, T. Q., Che, N., Wierer, M., Seldin, M. M., et al. (2021). Transcription Factor MAFF (MAF Basic Leucine Zipper Transcription Factor F) Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism. Circulation, 143(18), 1809-1823. doi:10.1161/CIRCULATIONAHA.120.050186.

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 Creators:
von Scheidt, Moritz1, Author
Zhao, Yuqi1, Author
de Aguiar Vallim, Thomas Q.1, Author
Che, Nam1, Author
Wierer, Michael2, Author              
Seldin, Marcus M.1, Author
Franzen, Oscar1, Author
Kurt, Zeyneb1, Author
Pang, Shichao1, Author
Bongiovanni, Dario1, Author
Yamamoto, Masayuki1, Author
Edwards, Peter A.1, Author
Ruusalepp, Arno1, Author
Kovacic, Jason C.1, Author
Mann, Matthias2, Author              
Bjorkegren, Johan L. M.1, Author
Lusis, Aldons J.1, Author
Yang, Xia1, Author
Schunkert, Heribert1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: Cardiovascular System & Cardiology; atherosclerosis; chromatin immunoprecipitation; coronary artery disease; inflammation; lipopolysaccharides; mafF transcription factor; receptors; LDL;
 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 characterize central regulators and networks leading to atherosclerosis. Methods: Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knockout models) and human (as shown by genome-wide association studies), 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, chromatin immunoprecipitation mass spectrometry, overexpression, small interfering RNA 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 (MAF basic leucine zipper transcription factor F) interacted as a key driver of a liver network with 3 human genes at CAD genome-wide association studies loci and 11 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 [Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task]) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested in noninflammatory conditions and showed positive correlation between MAFF and LDLR in vitro and in vivo. Interestingly, after lipopolysaccharide stimulation (inflammatory conditions), an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. Chromatin immunoprecipitation mass spectrometry revealed that the human CAD genome-wide association studies candidate BACH1 (BTB domain and CNC homolog 1) assists MAFF in the presence of lipopolysaccharide stimulation with respective heterodimers binding at the MAF recognition element 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.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published in print
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: Circulation
Source Genre: Journal
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Publ. Info: TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA : LIPPINCOTT WILLIAMS & WILKINS
Pages: - Volume / Issue: 143 (18) Sequence Number: - Start / End Page: 1809 - 1823 Identifier: ISSN: 0009-7322