Dataset Information

Transcription Factor Hepatocyte Nuclear Factor-1? Regulates Renal Cholesterol Metabolism.

ABSTRACT: HNF-1? is a tissue-specific transcription factor that is expressed in the kidney and other epithelial organs. Humans with mutations in HNF-1? develop kidney cysts, and HNF-1? regulates the transcription of several cystic disease genes. However, the complete spectrum of HNF-1?-regulated genes and pathways is not known. Here, using chromatin immunoprecipitation/next generation sequencing and gene expression profiling, we identified 1545 protein-coding genes that are directly regulated by HNF-1? in murine kidney epithelial cells. Pathway analysis predicted that HNF-1? regulates cholesterol metabolism. Expression of dominant negative mutant HNF-1? or kidney-specific inactivation of HNF-1? decreased the expression of genes that are essential for cholesterol synthesis, including sterol regulatory element binding factor 2 (Srebf2) and 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr). HNF-1? mutant cells also expressed lower levels of cholesterol biosynthetic intermediates and had a lower rate of cholesterol synthesis than control cells. Additionally, depletion of cholesterol in the culture medium mitigated the inhibitory effects of mutant HNF-1? on the proteins encoded by Srebf2 and Hmgcr, and HNF-1? directly controlled the renal epithelial expression of proprotein convertase subtilisin-like kexin type 9, a key regulator of cholesterol uptake. These findings reveal a novel role of HNF-1? in a transcriptional network that regulates intrarenal cholesterol metabolism.

SUBMITTER: Aboudehen K

PROVIDER: S-EPMC4978044 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Transcription Factor Hepatocyte Nuclear Factor-1β Regulates Renal Cholesterol Metabolism.

Aboudehen Karam K Kim Min Soo MS Mitsche Matthew M Garland Kristina K Anderson Norma N Noureddine Lama L Pontoglio Marco M Patel Vishal V Xie Yang Y DeBose-Boyd Russell R Igarashi Peter P

Journal of the American Society of Nephrology : JASN 20151228 8

HNF-1β is a tissue-specific transcription factor that is expressed in the kidney and other epithelial organs. Humans with mutations in HNF-1β develop kidney cysts, and HNF-1β regulates the transcription of several cystic disease genes. However, the complete spectrum of HNF-1β-regulated genes and pathways is not known. Here, using chromatin immunoprecipitation/next generation sequencing and gene expression profiling, we identified 1545 protein-coding genes that are directly regulated by HNF-1β in ...[more]

PMID: 26712526

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Project description:BackgroundCoronary 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.MethodsBased 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.ResultsThe 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.ConclusionsThe 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.

Dataset Information

Transcription Factor Hepatocyte Nuclear Factor-1? Regulates Renal Cholesterol Metabolism.

Publications

Transcription Factor Hepatocyte Nuclear Factor-1β Regulates Renal Cholesterol Metabolism.

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