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Transcription Factor Hepatocyte Nuclear Factor–1Β Regulates

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Transcription Factor Hepatocyte Nuclear Factor–1Β Regulates BASIC RESEARCH www.jasn.org Transcription Factor Hepatocyte Nuclear Factor–1b Regulates Renal Cholesterol Metabolism † ‡ Karam Aboudehen,* Min Soo Kim, Matthew Mitsche,§ Kristina Garland,§ | ‡ Norma Anderson,§ Lama Noureddine,* Marco Pontoglio, Vishal Patel,* Yang Xie, † Russell DeBose-Boyd,§¶ and Peter Igarashi* ** Departments of *Internal Medicine, ‡Clinical Sciences, §Molecular Genetics, and **Pediatrics and ¶Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas; †Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; and |Department of Development, Reproduction and Cancer, National Institute of Health and Medical Research (INSERM) U1016, The National Center for Scientific Research (CNRS) Joint Research Unit (UMR) 8104, University of Paris Descartes, Institut Cochin, Paris, France ABSTRACT HNF-1b is a tissue–specific transcription factor that is expressed in the kidney and other epithelial organs. Humans with mutations in HNF-1b develop kidney cysts, and HNF-1b regulates the transcription of several cystic disease genes. However, the complete spectrum of HNF-1b–regulated genes and pathways is not known. Here, using chromatin immunoprecipitation/next generation sequencing and gene expression pro- filing, we identified 1545 protein-coding genes that are directly regulated by HNF-1b in murine kidney epi- thelial cells. Pathway analysis predicted that HNF-1b regulates cholesterol metabolism. Expression of dominant negative mutant HNF-1b or kidney-specificinactivationofHNF-1b 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-1b mutant cells also expressed lower levels of cholesterol biosynthetic intermediates and had a lower rate of cholesterol synthesis than control cells. Addi- tionally, depletion of cholesterol in the culture medium mitigated the inhibitory effects of mutant HNF-1b on the proteins encoded by Srebf2 and Hmgcr, and HNF-1b 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-1b in a transcriptional network that regulates intrarenal cholesterol metabolism. J Am Soc Nephrol 27: 2408–2421, 2016. doi: 10.1681/ASN.2015060607 Hepatocyte nuclear factor-1b (HNF-1b) is a tissue– transcriptional activation involves the recruitment of specific transcription factor that is expressed in epithe- coactivators that include P/CAF, CBP, p300, lial cells in the liver, kidney, genital tract, pancreas, and zyxin.2,5 b lung, and intestine.1 In the mammalian kidney, HNF-1 is essential for the proper embryonic 6–8 HNF-1b is expressed in tubular epithelial cells in all development of the kidney. In the developing segments of the nephrons and renal collecting ducts. Received June 1, 2015. Accepted November 11, 2015. HNF-1b contains an N–terminal dimerization Published online ahead of print. Publication date available at domain, a Pit-1/Oct-1/Unc-86 homeodomain that www.jasn.org. mediates binding to the consensus sequence Present address: Dr. Lama Noureddine, Department of Internal (59-RGTTAATNATTAACM-39), and a C–terminal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa. transactivation domain.2 HNF-1b has been shown Correspondence: Dr. Peter Igarashi, Department of Medicine, to function as either a transcriptional activator or a 420 Delaware Street SE, MMC 194, Minneapolis, MN 55455. transcriptional repressor depending on the target Email: [email protected] – gene and cellular context.2 4 One mechanism for Copyright © 2016 by the American Society of Nephrology 2408 ISSN : 1046-6673/2708-2408 JAmSocNephrol27: 2408–2421, 2016 www.jasn.org BASIC RESEARCH mouse kidney, HNF-1b is expressed in nephron precursors IgG.16 Quality control of the ChIP-seq experiments is shown and the branching ureteric bud that gives rise to the renal in Supplemental Table 1. We found a total of 10,250 peaks collecting system. Loss-of-function mutations in Hnf-1b representing significantly enriched HNF-1b binding sites cause renal agenesis, in part, because of reduced expression (FDR,0.01). We then determined the spatial distribution of of Wnt9b, a ureteric bud–derived factor that is required for the HNF-1b binding peaks relative to annotated genes in the the induction of new nephrons.7 Expression of dominant mouse genome. The majority of HNF-1b binding sites were negative mutant HNF-1b disrupts renal tubulogenesis be- located close to or within genes (48% gene bodies, 6% gene cause of deregulated expression of the target gene Socs3.4 promoters, 7% upstream regions, and 4% downstream re- HNF-1b also plays a role in nephron patterning through gions) (Figure 1A). The remainder of the peaks (35%) mapped regulation of Notch signaling.9 to intergenic domains. Humans with heterozygous mutations in HNF-1b de- Next, we mapped the HNF-1b binding sites to known velop congenital kidney anomalies, including renal agenesis, mRNA and miRNA transcripts. Binding sites were linked hypoplasia/dysplasia, multicystic renal dysplasia, and glomer- to a gene if they were located within 50 kb upstream of the ulocystic kidney disease.10,11 A common feature is the forma- transcription start site or within the body of the gene. Binding tion of kidney cysts derived from the renal tubules. This cystic sites were linked to an miRNA if there was no intervening phenotype is recapitulated in the mouse by transgenic expres- gene between the binding site and the miRNA. On the basis sion of dominant negative mutant HNF-1b or kidney-specific of these criteria, in total, 4725 mRNAs and 85 miRNAs were inactivation of Hnf-1b.12,13 HNF-1b regulates the expression mapped to the HNF-1b binding peaks (Figure 1B). We per- of genes encoding ciliary proteins that have been implicated in formed quantitative ChIP to validate the ChIP-seq results cyst formation, including PKD2 and PKHD1.12,13 Moreover, for a representative sample of the target genes (Supplemental we have recently reported that HNF-1b regulates the activity Figure 1A). of the Pkhd1 promoter in the kidney in vivo.14 Active enhancers can be distinguished by epigenetic In the adult kidney, HNF-1b is expressed in renal tubular marks, such as histone H3 lysine 4 monomethylation and epithelial cells composing the nephron and collecting ducts, lysine 27 acetylation,17,18 as well as binding of RNA poly- where it regulates the expression of tissue-specific genes, in- merase 2.19 We determined whether the HNF-1b binding cluding Ksp-cadherin, collectrin, and solute transporters.1,15 sites that were identified by ChIP-seq overlapped with active Several physiologically relevant gene targets have been identi- enhancer marks in the kidney identified from the mouse fied in the kidney, primarily through identification of the con- ENCODE Project.20 Using this approach, in total, 6501 en- sensus recognition sequence in candidate gene promoters hancers were identified in the mouse kidney, of which 680 (e.g., NKCC2, FXYD2, OAT3/4,andURAT1). However, the were occupied by HNF-1b (Figure 1C). Supplemental Figure complete spectrum of genes and networks that are directly 1C depicts an example of an active enhancer located between regulated by HNF-1b is still not known. Psat1 and Cep78 genes showing colocalization with HNF-1b Here, we used chromatin immunoprecipitation (ChIP) binding. followed by next generation sequencing (ChIP sequencing To determine the consensus HNF-1b binding sequence in [ChIP-seq]) combined with gene expression profiling to our ChIP-seq dataset, we extracted the sequence elements and identify genes that are directly regulated by HNF-1b in renal performed motif analysis. When we examined binding sites in epithelial cells. These studies unexpectedly revealed that HNF- gene bodies and intergenic domains, only the half–site con- 1b directly regulates the expression of multiple genes that sensus motif for HNF-1b was over-represented. However, are required for cholesterol synthesis. We also found evidence when we examined peaks extracted from promoter regions, for a role of HNF-1b in the regulation of cholesterol uptake by the full HNF-1b consensus motif was significantly enriched transcriptional activation of proprotein convertase subtilisin–like (Supplemental Figure 1D). kexin type 9 (Pcsk9). Identification of Genes That Are Directly Regulated by HNF-1b RESULTS To identify genes that are regulated by HNF-1b,weper- formed microarray analysis on HNF-1b mutant cells. RNA Identification of HNF-1b Binding Sites in Kidney Cells was extracted from renal epithelial cells (53A cells) To identify HNF-1b binding sites at the whole-genome level, expressing a dominant negative HNF-1b mutant lacking we performed ChIP-seq analysis on mIMCD3 renal epithelial the C–terminal transcriptional activation domain (HNF- cells. Chromatin was isolated from mIMCD3 cells, cross- 1bDC),2,4 and gene expression profiles were compared linked, and immunoprecipitated with an anti–HNF-1b anti- with uninduced cells. Expression of the HNF-1bDCmu- body. After reversing the crosslinks, the immunoprecipitated tant altered the expression of 4878 mRNAs, of which 2610 DNA was subjected to next generation sequencing. Binding were downregulated and 2268 were upregulated (Figure sites were identified by enrichment of genomic sequences 1D). We validated the microarray results by performing compared with input and
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