Abstract
Urea cycle converts ammonia, a waste product of protein catabolism and a neurotoxin, into non-toxic urea. Urea cycle disorders are a group of rare genetic diseases that have protein-restricted diet as a common treatment modality. Expression of urea cycle genes is regulated in concert by the dietary protein intake, but the mechanism of this regulation is not well understood. Data mining of databases such as ENCODE and Cistrome can be used to gain new information about regulatory elements, transcription factors, and epigenetic mechanisms that regulate expression of urea cycle genes. This can lead to better understanding of the common mechanism, which regulates urea cycle genes, and can generate testable hypotheses about regulation of gene expression and new treatments for urea cycle disorders.
Keywords
- urea cycle
- transcriptional regulation
- transcription factor
- data mining
- ChIP-Seq
- epigenetic
- histone modification
- chromatin remodeler
1. Introduction
Transcriptional regulation of gene expression is essential for development, tissue differentiation, and organisms’ responses to changes in their environment. Maintenance of homeostasis would be impossible without regulation of expression of genes that code for enzymes in the carbohydrate, fat, and protein metabolism. Omnivorous mammals, such as humans, mice, and rats, can adapt their metabolism to varying proportions of amino acids, fats, and carbohydrates as sources of energy [1, 2]. Strict carnivores, such as cats, lack such adaptive mechanisms [3]. Diet rich in carbohydrates and fats triggers utilization of these nutrients as sources of energy and storage of excess sugars and fat in the form of glycogen and adipose tissue [1, 4]. On the other hand, a diet rich in proteins imposes changes in nitrogen balance because excess proteins and amino acids cannot be stored [1]. High intake of proteins, combined with low intake of carbohydrates and fats, leads to utilization of amino acids as energy sources and results in increased catabolism of amino acids [1, 4] and increased need to dispose of waste nitrogen, generated in this process. Transcriptional regulation of expression of enzymes in the pathways for degradation of nutrients as well as biosynthesis of molecules that can be stored is necessary for adaptations to these dietary changes.
Urea cycle is a liver metabolic pathway that converts ammonia into urea. Ammonia is a waste product of catabolism of dietary and cellular proteins, and a potent neurotoxin [5]. Defects in any of the enzymes of the urea cycle lead to partial or complete block of urea production and accumulation of ammonia, which damages the brain and can be lethal [5]. Therefore, the physiological role of urea cycle is to protect the brain from the toxic effects of ammonia.
Five enzymes of the urea cycle, carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthase (ASS), argininosuccinate lyase (ASL) and arginase 1, catalyze conversion of ammonia into urea. In addition, N-acetylglutamate synthase (NAGS), ornithine/citrulline transporter (ORNT), and aspartate/glutamate transporter (also known as ARALAR2 or Citrin) are required for the normal function of the urea cycle. The pathway is partitioned between mitochondria and cytoplasm of the liver cells. NAGS, CPS1, and OTC are located in the mitochondrial matrix [6] while ASS, ASL, and arginase 1 are in the cytosol [6]. Figure 1 shows enzymes, transporters, and intermediates of the urea cycle together with their cellular localization. The NAGS (EC 2.3.1.1) uses glutamate and acetyl coenzyme A to produce NAG, an obligatory allosteric activator of CPS1 [6, 7, 8, 9]. Upon binding of NAGS, CPS1 (EC 6.3.4.16) consumes two molecules of ATP to catalyze formation of carbamoyl phosphate from ammonia and bicarbonate [6, 10]. Carbamoyl phosphate and ornithine, which is transported into mitochondria by ORNT, are converted to citrulline by OTC (EC 2.1.3.3), followed by the transport of citrulline from mitochondria into cytoplasm by ORNT [6]. ASS (EC 6.3.4.5) catalyzes formation of argininosuccinate from citrulline and aspartate, which is supplied by the Citrin [6]. The argininosuccinate is then converted to arginine by the ASL (EC 4.3.2.1). Arginase 1 (EC 3.5.3.1) completes the cycle by hydrolyzing arginine into urea and ornithine, which is transported into mitochondria to be a substrate for OTC (Figure 1). Urea cycle genes and enzymes are not uniformly expressed in the liver; their expression follows a gradient from high in hepatocytes surrounding portal vein to no expression in hepatocytes surrounding central vein [11]. NAGS, CPSI, and OTC are also expressed in the small intestine, where they synthesize citrulline which is then transported to the kidneys for the biosynthesis of arginine by the ASS and ASL [6]. Argininosuccinate synthase and lyase also function in the NO signaling and are present in the tissues that express nitrous oxide synthase [5].
Long-term changes in dietary protein intake lead to adaptive changes in expression of urea cycle enzymes. Their expression increases in rats and monkeys fed high-protein diet and decreases upon feeding of low-protein diet [4, 12]. These adaptive changes seem to be mediated, at least in part, by the hormones glucagon, glucocorticoid, and insulin [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25]. Glucagon and glucocorticoid hormones trigger changes in mRNA and protein levels of all five urea cycle enzymes, but the mechanisms responsible for these changes seem to differ for each enzyme [21]. It is not known whether changes in the dietary protein intake trigger similar changes in the expression of the NAGS gene because it has not been identified at the time. Also unknown are signaling cascades that mediate effects of hormones to regulate expression of urea cycle genes and whether specific amino acids and/or other metabolites act as sensors of the dietary protein intake.
Inspection of the regulatory regions of genes for urea cycle enzymes (Figure 2) does not reveal a common regulatory element that would bind one or more transcriptional factors to coordinately regulate transcription of all urea cycle genes [13, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36]. The studies of expression of urea cycle genes in knockout mice also show a lack of common regulatory mechanism. Ureagenesis is defective in mice lacking hepatocyte nuclear factor 4 α (HNF4α) due to absence of OTC mRNA and protein [37] as well as in mice lacking CCAAT/enhancer binding protein α (C/EBPα) due to lack of CPSI mRNA [38]. However, ureagenesis appears normal in mice lacking C/EBPβ although this transcriptional factor appears to regulate expression of the arginase 1 gene [39]. It is also unknown if short-term increases in nitrogen load following a meal trigger any change in expression of urea cycle enzymes.
This chapter focuses on the regulation of NAGS, CPS1, and OTC expression because their only known functions are protection of the brain from ammonia toxicity through participation in the urea cycle and intestinal biosynthesis of citrulline. The three genes share common expression pattern in the liver, intestine, and during development. Because of the role of urea cycle in protecting the brain from ammonia toxicity, expression of the three genes have been studied in much greater detail in the liver than intestinal cells. Detailed understanding of the transcriptional regulation of the urea cycle genes is important for our understanding of bodies’ response to changes in the environment such as dietary changes as well as events that trigger increased catabolism of cellular proteins such as starvation, infections, and invasive medical procedures [6, 40, 41, 42, 43]. Because regulation of expression of the mammalian CPS1 and OTC genes has been studied for more than three decades while expression of human NAGS, which was identified and cloned in 2002, took place less than a decade ago the approaches taken in these studies differed greatly. Knowledge of transcriptional regulation of mammalian CPS1 and OTC was gained through cloning of genomic DNA, construction of reporter gene plasmids with various fragments from the CPS1 and OTC regulatory regions and their expression in cultured cells and transgenic mice, whereas regulatory elements of the NAGS gene have been identified using comparative genomics approaches.
2. Transcriptional regulation of urea cycle genes
2.1. Transcriptional regulation of mammalian NAGS gene
Although the existence of mammalian NAGS gene and its product have been known since the 1950s [44], the gene remained elusive until 2002, when it was identified and cloned in mice and humans [45, 46, 47, 48]. The human
Reporter gene assays were used to confirm that conserved regions located adjacent to and −3 kb upstream of the first
2.2. Transcriptional regulation of mammalian CPS1 gene
Regulatory region of the rat
A promoter, located immediately upstream of the first
2.3. Transcriptional regulation of mammalian OTC gene
The human
The rat
2.4. Transcriptional regulation of the NAGS, CPS1, and OTC genes in the genomics era
Advances in sequencing technology-enabled sequencing of dozens of mammalian genomes and comparisons of their sequences revealed conserved regions in non-coding regions that could function as regulatory elements [72, 73]. This strategy was used to identify NAGS promoter and enhancer [50]. Next-generation sequencing also enabled examination of the function of non-coding regions in the human and mouse genomes including their chromatin structure, and binding of transcription and chromatin remodeling proteins to generate an Encyclopedia of Non-coding DNA Elements (ENCODE). These studies were first carried out in the limited number of cultured cell lines, but are now expanding to include tissues and cultured primary cells and their results have been stored in the ENCODE database [74, 75]. In addition to these large-scale projects, many individual labs have been performing ChIP-Seq experiments and the publically available results of their experiments are being gathered in the Cistrome database [76]. The advantage of the Cistrome database is ability to compare chromatin states and track changes in binding of transcription factors in response to signaling molecules, treatments, and environmental stimuli. Data mining of the ENCODE and Cistrome databases present an opportunity to identify novel regulatory elements in the
The 5′-ends of each region were chosen based on the presence of RAD21, a component of cohesion, and CTCF binding that can indicate boundaries of chromatin domains, whereas the 3′-ends of the
The H3K4me3 histone 3 modifications that mark active promoters and H3K27ac modifications that mark active enhancers are present at upstream regions of all three genes (Figures 3B, 4B, and 5B). The ENCODE database also has the DNaseI sensitivity data from the human fetal liver tissue that show open chromatin state for the
Query of the ChIP-Seq data in the ENCODE database confirmed binding of the Sp1, CREB/ATF3, HNF4A, HNF3/FOXA1, HNF3/FOXA2, and COUP-TF to the promoters and enhancers of the
Transcription factors HNF3/FOXA1, HNF3/FOXA2, and CREB bind to the human
These data mining efforts identified a common set of transcription factors that bind to the regulatory regions of the
Acknowledgments
This work was supported by public health service grants K01DK076846 and R01DK064913 from the National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services.
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