TY - JOUR
T1 - Transcription Factor MAFF (MAF Basic Leucine Zipper Transcription Factor F) Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism
AU - von Scheidt, Moritz
AU - Zhao, Yuqi
AU - de Aguiar Vallim, Thomas Q
AU - Che, Nam
AU - Wierer, Michael
AU - Seldin, Marcus M
AU - Franzén, Oscar
AU - Kurt, Zeyneb
AU - Pang, Shichao
AU - Bongiovanni, Dario
AU - Yamamoto, Masayuki
AU - Edwards, Peter A
AU - Ruusalepp, Arno
AU - Kovacic, Jason C
AU - Mann, Matthias
AU - Björkegren, Johan L M
AU - Lusis, Aldons J
AU - Yang, Xia
AU - Schunkert, Heribert
N1 - M.V.S. reports funding from the Clinician Scientist Excellence Program of the
German Center for Cardiovascular Research, the German Society of Cardiology,
and the German Heart Foundation. This work was supported by grants from
the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02),
the Bavarian State Ministry of Health and Care through the research project
DigiMed Bayern (www.digimed-bayern.de), the Bavarian State Ministry of
Science and the Arts through the research project Deutsches Herzzentrum
München and Munich School of Robotics and Machine learning Joint Research
Center, the German Federal Ministry of Education and Research within the
framework of European Research Area Network on Cardiovascular Disease,
Joint Transnational Call 2017 (European Research Area–Cardiovascular-Disease:
grant JTC2017_21-040) within the framework of target validation (BlockCAD:
16GW0198K) and within the framework of the e:Med research and funding
concept (Aberrant transcriptome influencing risk of common diseases - Network: grant 01ZX1706C and e:AtheroSysMed, grant 01ZX1313A-2014); further
funding was provided from the Deutsche Forschungsgemeinschaft directly
(SA 1668/5-1), and as part of the Sonderforschungsbereich Collaborative
Research Centre 1123 (B2), and the German Heart Research Foundation
[F/28/17] (to H.S.). Maff work is supported by National Institutes of Health grant
DK102559 (to T.Q.d.e.A.V. and P.A.E.). Bioinformatics work was supported by
the American Heart Association Postdoctoral Fellowship (to Y.Z.) and National
Institutes of Health grants DK104363 (to X.Y.). The STARNET (StockholmTartu Atherosclerosis Reverse Network Engineering Task) study was supported
by the University of Tartu (development fund: SP1GVARENG), the Estonian
Research Council (ETF grant 8853), the Astra-Zeneca Translational Science
Center-Karolinska Institutet (a joint research program in translational science),
Clinical Gene Networks AB as a small and medium-sized enterprise of the FP6/
FP7 EU-funded integrated project CVgenes@target (HEALTH-F2-2013-601456),
the Leducq transatlantic networks, CADgenomics, the American Heart
Association (A14SFRN20840000), the National Institutes of Health National
Heart, Lung, and Blood Institute (R01HL125863; R01HL71207; R01AG050986;
K08HL111330; to J.L.M.B.). In vitro and hybrid mouse diversity panel work was
supported by National Institutes of Health grants HL138196 (to M.M.S.); and
HL28481, HL30568, HL144651, HL147883, and DK117850 (to A.J.L.)
PY - 2021/5/4
Y1 - 2021/5/4
N2 - 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.
AB - 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.
KW - atherosclerosis
KW - chromatin immunoprecipitation
KW - coronary artery disease
KW - inflammation
KW - lipopolysaccharides
KW - mafF transcription factor
KW - receptors, LDL
KW - Cardiology and Cardiovascular Medicine
KW - Physiology (medical)
UR - https://www.mendeley.com/catalogue/fd427453-7c96-35f9-a0da-95b70020db73/
UR - http://www.scopus.com/inward/record.url?scp=85105512338&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.120.050186
DO - 10.1161/CIRCULATIONAHA.120.050186
M3 - Article
C2 - 33626882
SN - 0009-7322
VL - 143
SP - 1809
EP - 1823
JO - Circulation
JF - Circulation
IS - 18
ER -