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Departments of Nutritional Sciences and Molecular and Cellular Biology, The University of Connecticut, Storrs, CT 06269
3To whom correspondence should be addressed. E-mail: mmcgrane{at}canr.uconn.edu.
ABSTRACT
Vitamin A deficiency decreases hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene expression in mice, and expression is restored with retinoic acid (RA) treatment in vivo. In the studies reported here, we examined changes in histone modification and coregulator association with the regulatory domains of the PEPCK gene in response to alterations in vitamin A status. We identified nuclear receptors that bind to retinoic acid response elements (RAREs) in the PEPCK promoter by electrophoretic mobility shift assay and verified these in vivo using chromatin immunoprecipitation in mouse liver. Hypothetically, nuclear receptors at PEPCK RAREs recruit specific coactivator molecules that contribute to the acetylation of core histones and/or serve as bridging molecules between nuclear receptors and basal transcription factors at the transcription start site. We identified 3 coactivator molecules, cAMP-response element binding protein (CBP), steroid receptor coactivator (SRC)-1, and peroxisome-proliferator activated receptor (PPAR)-
-coactivator (PGC)-1
, that bound in association with the PEPCK RAREs in vivo. Furthermore, there was differential binding of these coactivators in vitamin A–deficient mice. Related to this, specific lysine residues were acetylated on histones H3 and H4 at the 3 RAREs of the PEPCK promoter, consistent with the action of the above coactivators, and acetylation of certain lysines was significantly decreased with vitamin A deficiency. These results demonstrate the associated changes that occur in nuclear receptor binding, coactivator recruitment, and histone acetylation in response to vitamin A status, identified at specific RAREs in the PEPCK gene in vivo.
KEY WORDS: • vitamin A • phosphoenolpyruvate carboxykinase gene • histone acetylation • coactivators
Cytosolic phosphoenolpyruvate carboxykinase [PEPCK4 (EC 4.1.1.32)] catalyzes the conversion of oxaloacetate to phosphoenolpyruvate in the first committed step in hepatic gluconeogenesis. In addition to hormonal regulation, in vitro and in vivo studies have shown that hepatic PEPCK gene expression is also regulated by vitamin A (1–7). Retinoids exert their influence on PEPCK gene transcription through the binding of nuclear receptors to 3 identified retinoic acid response elements (RAREs) in the PEPCK promoter. It is generally accepted that nuclear receptors provide a physical weakening of histone/DNA interactions in chromatin through direct DNA binding and through their recruitment of specific coregulatory molecules. Most coactivator molecules increase gene transcription via histone acetyltransferase (HAT) activity, chromatin remodeling, and/or their ability to serve as bridging factors between nuclear receptors and the RNA Polymerase II (RNA Pol II) complex at the transcription start site. Models outlining the mechanism of regulated gene expression have been proposed, but the precise sequence of these events remains undefined for specific genes (8,9). However, it is becoming increasingly clear that individual coactivators function as part of cohesive multiprotein complexes to increase gene transcription and that the exact process may be unique to individual gene promoters (10). Similar functional complexes may also assemble at regulatory domains of genes that are involved in the same metabolic pathways.
Coactivators that have been implicated in regulation of the PEPCK gene include peroxisome proliferator-activated receptor (PPAR)--coactivator (PGC)-1 (11,12), cAMP response element binding protein (CBP) (13), and steroid receptor coactivator (SRC)-1 (14). In this report, we explored the molecular mechanism that underlies retinoid-mediated regulation of the mouse PEPCK gene in vivo with native chromatin structure intact. We found that vitamin A deficiency altered histone acetylation and coactivator binding, and this was correlated with decreased RNA Pol II association and PEPCK gene expression.
MATERIALS AND METHODS
Animal treatments. To generate vitamin A–deficient (VAD) mice, pregnant C57BL/6J mice (Jackson Laboratories) were fed the AIN93G diet (15) without vitamin A (Dyets) from d 10 of gestation until the pups were weaned. Pups continued to consume the VAD diet until they were killed by cervical dislocation at 9–10 wk of age. Vitamin A–sufficient (VAS) mice were fed the complete AIN93G diet.
Three hours before chromatin isolation, VAD mice undergoing retinoid treatments were supplemented with a total of 10 mg/kg body weight of all-trans retinoic acid (RA) (Sigma-Aldrich), 9-cis RA (Toronto Research Chemicals) or both, delivered in peanut oil by gavage, with control counterparts administered only peanut oil. Total volumes did not exceed 180 µL. All mice (VAS, VAD, and treated) were food deprived for 15 h before they were killed.
The above protocols were approved by the Institutional Animal Care and Use Committee at the University of Connecticut (Animal Care Protocol #E1200501).
Chromatin immunoprecipitation (ChIP) assay. The ChIP assay was conducted using mouse liver based on the methods of Farnham and colleagues (16) and Bennett and Osborne (17) with the following modifications for liver. Dissected livers were minced and crosslinked with 1% formaldehyde. Crosslinking was stopped with 125 mmol/L glycine and samples were rinsed with 1X PBS containing 1 mmol/L phenylmethylsulfonyl fluoride (PMSF) and disaggregated with a Dounce homogenizer. Cells were pelleted and resuspended in lysis buffer [5 mmol/L PIPES (8.0), 85 mmol/L KCl, 0.5% Igepal, 0.5 mmol/L PMSF, 0.16 µmol/L protease inhibitor cocktail (Sigma-Aldrich)] and dounced to aid nuclei release. The nuclei were pelleted by centrifugation at 4500 x g for 5 min and lysed by resuspension in nuclear lysis buffer [50 mmol/L Tris (8.0), 10 mmol/L EDTA, 1% (wt/vol) SDS with the above protease inhibitors]. Samples were divided into aliquots (250 µL) and sonicated on ice by pulsing 4 times for 5-s intervals using a Fisher Model 60 sonicator (Fisher Scientific) to generate DNA fragments averaging 400–500 bp in length. After sonication, the samples were clarified and adjusted to a concentration of 25 A260 kU/L.
To reduce nonspecific binding, the chromatin was precleared twice by incubation with either recombinant protein A or G (or A and G) sepharose (Zymed Laboratories), depending on the primary antibody to be used in the immunoprecipitation step. The sepharose was pretreated with salmon sperm DNA and bovine serum albumin to block nonspecific binding.
The equivalent of 0.03 g of liver, corresponding to 
12 µg input chromatin, was used in each ChIP assay when primary antibodies specific to histones H3 and H4 (Upstate Biotechnology) were used. To obtain more visible signals by PCR, the equivalent of 0.04 g of liver (16 µg input chromatin) was used in ChIP assays conducted for proteins present in lower abundance in liver (i.e., PGC-1, CBP, and SRC-1), while the ratio of input chromatin to Protein A and/or G Sepharose beads was kept constant. Immunoprecipitation was carried out at 4°C overnight on a rotating wheel followed by incubation with protein A, G, or a mixture of A and G sepharose for 2 h at 4°C with rotation. The samples were washed several times and eluted using a microspin chromatography column (BioRad Laboratories) with elution buffer (1% SDS, 50 mmol/L NaHCO3) at 65°C. The optimal amounts of antibody used in each ChIP assay were determined empirically.
To reverse the formaldehyde crosslinks in the immunoprecipitated DNA, the NaCl concentration was adjusted to 0.3 mol/L, and 1 µL RNase A (10 mg/L) was added per 200 µL of original diluted chromatin. The samples were incubated at 65°C for 4 h. DNA was purified using the Qiaquick Purification Kit (Qiagen) and subjected to PCR.
PCR. PCR reactions (50 µL) contained 4 µL purified DNA from immunoprecipitated or negative control samples, along with 0.6 µmol/L of each primer, 200 µmol/L each dATP, dCTP, dGTP, and dTTP, 1X PCR buffer containing 1.5 mmol/L MgCl2, and 1.25 U HotStarTaq DNA Polymerase (Qiagen). After 29 cycles of PCR amplification with an annealing temperature of 57°C, PCR products were run on a 1.5% agarose gel, visualized, and quantified by ethidium bromide staining using Quantity One v.4.1 software (BioRad Laboratories). Primers used for the region encompassing mouse PEPCK RARE1/RARE2 were 5'-AGGTAAC ACACCCCAGCTAAC-3' and 5'-GGCTCTTGCCTTAATTGTCAG-3' and for mouse PEPCK RARE3, 5'-GGCATGAAGGTCTGTGGCTAC-3' and 5'-TAGACACCATCACCC TTGGAG-3'.
Northern analysis. Total RNA was isolated from liver using the method of Chomczynski and Sacchi (18). Northern blot analysis was performed as previously described (19), with slight modifications. Total RNA (10 µg) was separated on a formaldehyde-containing agarose gel and transferred overnight to a Gene Screen Plus® hybridization membrane (PerkinElmer Life Sciences) using downward capillary transfer and 10X SSC (20). Membranes were UV crosslinked using a commercial crosslinker (Stratagene) and baked at 80°C for 2 h. Radiolabeled probes were generated using a random primer labeling kit (Invitrogen) and either a 1.6-kb 32P-labeled BglII rat PEPCK fragment (21) or a 1.6-kb fragment of the rpL32 gene as a loading control. The membranes were exposed to Kodak Biomax MS film (Eastman Kodak) using a Transcreen HE intensifying screen (Eastman Kodak) at –80°C. Autoradiograms were quantified using Quantity One v.4.1 software (BioRad Laboratories).
Statistical analysis. For ChIP assays, results are reported as mean image densities ± SEM, with the negative control for each ChIP assay set to a value of 1. Using Northern analyses, results were quantified as the ratio between the densitometric signals measured for PEPCK and rpL32 control mRNAs and are presented as means ± SEM.
Differences between group means were analyzed using Student’s t test or one-way ANOVA and were considered significant at P < 0.05. Data were evaluated using MS Excel 2002 (Microsoft) or Prism4 (GraphPad Software).
RESULTS
Hepatic CBP, PGC-1, and SRC-1 bind PEPCK RARE1/RARE2.
In vivo binding of coactivators to the PEPCK RARE DNA elements was assessed using the ChIP assay. The ChIP assay was adapted for assessment of protein-DNA interactions in intact tissue, e.g., mouse liver, rather than in cultured cells. CBP, PGC-1, and SRC-1 are coactivators that interact with nuclear receptors at the PEPCK RAREs in vitro and are potentially involved in vitamin A regulation of the PEPCK gene. We examined the association of these coactivators with the PEPCK RAREs under conditions of vitamin A sufficiency and deficiency. CBP, PGC-1, and SRC-1 all showed an association with RARE1/RARE2 of the mouse PEPCK promoter in vivo (Fig. 1). Although CBP bound RARE1/RARE2 to the same extent in both VAS and VAD mice, SRC-1 binding to RARE1/RARE2 was lower in liver of VAD than in VAS mice (P = 0.02). The PGC-1 association with RARE1/RARE2 also tended to be lower in the liver of VAD mice (P = 0.06).
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is bound at PEPCK RARE3 and is significantly decreased in VAD liver.
Neither CBP nor SRC-1 bound at PEPCK RARE3 (data not shown), whereas PGC-1 was associated with RARE3 to the same degree as was measured for RARE1/RARE2 (Fig. 2). PGC-1 binding, however, was decreased in the liver of VAD mice at RARE3. There was a significant reduction in PGC-1 binding to RARE3 in liver of VAD mice (P = 0.05).
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DISCUSSION
We characterized the nuclear receptors that bind PEPCK RAREs by both in vitro and in vivo techniques, and determined changes in nuclear receptor binding to PEPCK RAREs with changes in vitamin A status, including a decrease in PPAR binding at RARE3 and, to a lesser extent, a decrease in PPAR and RAR binding at RARE1/RARE2 (Scribner and McGrane, unpublished observations). Hypothetically, it is not nuclear receptors themselves, but ligand binding to nuclear receptors that is significantly altered with changes in vitamin A status. Changes in ligand binding, in this case all-trans and/or 9-cis RA, should alter the ability of nuclear receptors to serve as docking sites for coactivators, thus altering the degree of acetylation of core histones in the nucleosomes of the RARE enhancer and promoter regions of the DNA. In this report, we demonstrated changes in coactivator association at PEPCK RAREs and decreases in acetylation of specific lysines present in the H3 histone tail within the core octamer of the nucleosomes at the RAREs in the PEPCK promoter. We found that histones H3 and H4 were acetylated at RARE1/RARE2 and RARE3 of the mouse PEPCK gene in vivo, with measurable differences in H3 acetylation in the liver of VAD mice. Of the lysine residues tested, K9 on H3 and K8 on H4 were acetylated, whereas K14 on H3 and K5, K12, and K16 on H4 did not show significant acetylation (Fig. 3). Selective acetylation of lysine residues on core histones, rather than global acetylation of all histones in an activated gene, corresponds to the concept of an inherent "histone code" in chromatin that is both tissue and gene specific (26–28). This programming is thought to rely on native chromatin structure, dictated by association with highly specialized coregulator proteins and dependent upon other post-translational histone modifications such as phosphorylation, methylation, or ubiquitylation (8,22,27–32). Thus, the acetylation of K9 on H3 and K8 on H4 is part of the histone code for PEPCK gene expression and the acetylation/deacetylation of K9 on H3 is dependent on vitamin A status in liver. Additionally, it was shown that acetylation of K9 on H3 precludes methylation of this lysine residue, thus precluding a type of covalent modification of H3 that is involved in gene repression (33). Our results are also consistent with those of Thanos and colleagues (34) who determined that a limited number of lysines, including K9 in H3 and K8 in H4, are acetylated in the promoter of the IFNß gene under conditions of active transcription. In the interferon ß promoter, acetylated K9 in H3 and K8 in H4, acting together, recruit the bromodomain-containing complexes involved in chromatin remodeling, SWI/SNF, and the general transcription factor TAFII250.
Based on the work presented here, decreased PEPCK gene expression in vitamin A deficiency can be explained in part by a decrease in K9 acetylation in the amino termini of H3 histone tails of the nucleosomal structure at RARE1/RARE2. Hypothetically, this contributes to a tightened chromatin configuration and/or a decreased association of chromatin remodeling complexes, causing decreased RNA Pol II association; the latter is consistent with what we measured in the liver of VAD mice (24). This is possibly due to the lack of recruitment of a chromatin remodeling complex such as SWI/SNF and general transcription machinery components such as TAFII. In vitro studies identified many HATs that have the ability to acetylate numerous lysine residues on multiple histones, but it is still not clear whether these in vitro results correspond to what occurs in native chromatin in vivo (35–38). However, studies using free histones and isolated mononucleosomes showed that SRC-1 preferentially acetylates H3 at K9 and K14 (35,39), suggesting that the decreased SRC-1 binding at PEPCK RARE1/RARE2 measured in vitamin A deficiency (Fig. 1B) may be responsible for the decreased acetylation at K9 in the histone H3 tail.
CBP also has HAT activity and exhibits a substrate preference for specific lysines in histones. K8 on H4 serves as a substrate for acetylation by CBP in vitro (36–38). K8 was acetylated at the PEPCK promoter in vivo, with no alteration in K8 acetylation in VAD mice. This is consistent with CBP being constitutively associated with the PEPCK promoter, regardless of changes in vitamin A status (Fig. 1B). Potentially, acetylation of H4 at K8 has a broader purpose for maintaining basal transcription of the PEPCK gene, whereas K9 acetylation in H3 is linked to changes in acute transcriptional regulation. Because CBP can also acetylate HNF-4 (40), it is possible that CBP participation in PEPCK gene regulation includes functionally relevant acetylation of nonhistone proteins that bind the RAREs. The coactivator PCAF also weakly acetylates H4 at K8 in vitro (38), but we were not able to detect PCAF binding to PEPCK RAREs in vivo (data not shown).
Coactivators with or without HAT capability can serve as links between DNA response elements and the transcription preinitiation complex (PIC) (29). PGC-1, which regulates many metabolic genes including PEPCK, does not possess intrinsic HAT activity, but does interact with nuclear receptors and coregulators that are associated with PEPCK gene expression (11–13,41–45). Like CBP (46–48) and SRC-1 (49), PGC-1 activates PEPCK gene expression and interacts with the PIC (50). PGC-1 binds both the upstream RARE3 and downstream RARE/RARE2 elements of the PEPCK gene in liver, and there is a decrease in this association at both the upstream and downstream elements in the liver of VAD mice. This is the first report of a liver coactivator binding to PEPCK RARE3 because this response element has been characterized only in adipose tissue, and is consistent with our earlier finding, also novel, that PPAR binds RARE3 in vivo (Scribner and McGrane, unpublished observation).
The evidence presented here provides us with a broader perspective on the effects of vitamin A deficiency on PEPCK gene expression. Previously, we showed that decreased PEPCK gene expression in VAD mice corresponds to an interrupted association of RNA Pol II at PEPCK RARE1/RARE2 under the same conditions in vivo (24). Subsequent reassociation of RNA Pol II at the PEPCK promoter occurs with the administration of physiologic doses of both all-trans and 9-cis RA and mirrors the increase we measured in PEPCK mRNA under the same conditions, as reported here. Therefore, all-trans and 9-cis RA, in combination, activate PEPCK gene transcription, mediated through differential regulation of the RAREs (25). We propose that vitamin A deficiency decreases PEPCK gene expression by decreasing both SRC-1 association at RARE1/RARE2 and PGC-1 association at RARE3 and potentially RARE1/RARE2, thereby disrupting components of the coactivator complex that are involved in histone acetylation, chromatin remodeling, and bridging the RAREs with the transcription start site. Thus, the decrease in SRC-1 binding at RARE1/RARE2 would constitute a decrease in localized HAT activity, and we measured a decrease in histone H3 K9 acetylation at RARE/RARE2, but not RARE3, under the same conditions. This, in turn, could lead to a decrease in the binding of chromatin remodeling complexes at RARE1/RARE2, and a decrease in chromatin remodeling at this region and downstream within the PEPCK promoter. The decrease in SRC-1 association could also weaken the bridge between the proximal RAREs and the PIC, slowing the rate of PIC assembly. Decreased PGC-1 would also contribute to weakening the multiprotein complex by its absence and decreasing recruitment of other accessory proteins that bridge the RAREs with the PIC, while leaving acetylation states unaffected. CBP, acting as a cointegrator, could be more strongly associated with the PEPCK promoter than are SRC-1 and PGC-1; CBP may be required, although not sufficient, for retinoid induction of the PEPCK gene. As stated previously, it could have a more integral role in maintaining basal acetylation of H3 and H4 lysines that are not deacetylated with VAD.
FOOTNOTES
1 Supported by U.S. Department of Agriculture Grant #2003–00883 (to M.M.M.). 
2 Current address: Endocrinology–Obesity Program, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115.
4 Abbreviations used: CBP, cAMP-response element binding protein; ChIP, chromatin immunoprecipitation; HAT, histone acetyltransferase; K, lysine; PEPCK, phosphoenolpyruvate carboxykinase; PGC, peroxisome proliferator-activated receptor- coactivator-1; PIC, preinitiation complex; PMSF, phenylmethylsulfonyl fluoride; PPAR, peroxisome proliferator-activated receptor; RA, retinoic acid; RAR, retinoic acid receptor; RARE, retinoic acid response element; RNA Pol II, RNA polymerase II; RXR, retinoid X receptor; SRC-1, steroid receptor coactivator-1; VAD, vitamin A–deficient; VAS, vitamin A–sufficient.
Manuscript received 29 May 2005. Initial review completed 29 June 2005. Revision accepted 13 August 2005.
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  T. Cadoudal, M. Glorian, A. Massias, F. Fouque, C. Forest, and C. Benelli Retinoids Upregulate Phosphoenolpyruvate Carboxykinase and Glyceroneogenesis in Human and Rodent Adipocytes J. Nutr., June 1, 2008; 138(6): 1004 - 1009. [Abstract] [Full Text] [PDF]
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