| | Transcriptional regulation of peptidylarginine deiminase expression in human keratinocytesReceived 10 July 2008; received in revised form 25 August 2008; accepted 19 September 2008. Abstract Peptidylarginine deiminase (PAD, EC 3.5.3.15) enzyme catalyzes the conversion of arginine residues to citrulline residues in the presence of calcium ion, which is an elaborate post-translational modification on the target protein. Recently, five isoforms have been identified in mammals. Among them, three isoforms (type I, II, III) are expressed in the human epidermis, and involved in several skin physiological and pathological processes. In the past few years, several researches concerning the transcriptional regulation of three human PADI type genes (PADI1, PADI2 and PADI3) in the epidermis have been carried out. In this review, we describe an overview of the current outcomes about these studies with their significance. It is anticipated that these investigations will provide novel therapeutic and prophylactic targets for future approaches to the treatment or prevention of severe psoriasis and bullous congenital ichthyosiform erythroderma. Abbreviations: BCIE, bullous congenital ichthyosiform erythroderma, ChIP, chromatin immunoprecipitation, EMSA, electrophoretic mobility-shift assay, MZF1, myeloid zinc finger 1, NF-Y, nuclear factor Y, NHEK, normal human epidermal keratinocyte, PAD, peptidylarginine deiminase, Sp1, specificity protein 1, Sp3, specificity protein 3, siRNA, small interfering RNA 1. Peptidylarginine deiminase  1.1. Introduction Post-translational modifications of protein are crucial because they may alter physical and chemical properties, folding, distribution, stability, activity, and consequently the functions of the targeted proteins, some of which being involved into diseases. Recently, one post-translational modification, deimination (also called citrullination), became of an increasing concern. Peptidylarginine deiminase (PAD, EC3.5.3.15) has been found as the enzyme that catalyzes deimination [1], [2], [3], the conversion of protein-bound arginine residues to citrulline residues in the presence of calcium ion (Fig. 1A). This modification dramatically alters the charge of residues from positive to neutral, probably resulting in loss of target conformation, in aggregation ability, or in depolymerization tendency. The typical examples, filaggrin [4] and S100A3 [5] are shown in Fig. 1B. 1.2. PAD gene family Recently, vertebrate PADs were categorized into five isoforms (PAD1, 2, 3, 4 and 6), based on their amino acid sequences, substrate specificities and tissue location [4], [6], [7], [8]. Meanwhile, with the development of genomic projects and advanced genomic prediction approach, it was found that only one potential PAD, similar to PAD2, exist in fish (Danio rerio, Takifugu rubripes and Tetraodon nigroviris) and amphibians (Xenopus laevis) [9]. Otherwise, there are three isotypes (cPad1–3) predicted in birds (Gallus gallus). In mammals, the chromosomal localization of all five types of PAD genes has been determined in mouse (Mus musculus), rat (Rattus norvegicus) and human (Homo sapiens). As shown in Fig. 2A, it seems that the number of PAD isotypes increases by the biological evolution. Furthermore, the phylogenetic tree of the PADI gene (encoding PADs) from available cDNA sequence data on NCBI was constructed using ClustalW, as shown in Fig. 2B. The PADI2 gene is likely to diverge first from the common ancestor, the other PADI gene being derived by duplication during phylogenetic development. This presumption is also consistent with phylogenetic analysis of PAD amino acid sequences [8], [9], [10]. Moreover, PADI2 is expressed in the broadest tissue distribution. This suggests that PAD2 retains an ancestral function. Aside, it is also speculated that the other PADI genes have evolve to be expressed in specific tissues and to target specific substrates. In human, all genes are located at a single cluster which spans an about 334.7 kb region on chromosome 1p36.1 Fig. 3A. PADI2 which shows a converse orientation to the other four PADIs, is the largest gene, while PADI6 is the smallest one. Each of the PADI genes has the same exon/intron structure, the genomic structure of the PAD gene cluster being conserved as well in all mammals. The high conservation of the amino acid sequences of PAD orthologs has also been demonstrated before [8], [9], [10]. 1.3. PADs in skin physiology and diseases Among the human PADs, only PAD type I (PAD1), type II (PAD2) and type III (PAD3) are expressed in the skin [11], [12], [13]. The precise cellular localization of these three isoforms has been described by confocal and immunoelectron microscopy analyses with highly specific antipeptide antibodies [6], [7], [8]. As shown as Fig. 3B, PAD1 was detected in the entire epidermis with an increasing intensity gradient from the basal to the granular layer. PAD2 was mainly detected in both the spinous and granular layers with a more intense staining of the latter, whereas PAD3 expression was shown to be restricted to the granular layer and lower stratum corneum (SC). PAD1 and PAD3 were also detected in the inner root sheath and cuticle of the hair follicles, whereas PAD3 was the only isoform expressed in the medulla [1], [7], [13]. The complex expression and distribution of these PADs indicate that they may perform different duties, and target specific substrates for a cooperative and complex work. The process of normal epidermal differentiation is characterized by a series of morphologic changes as keratinocytes progress from the germinative basal layer through the spinous and granular layers to the outer cornified layer. Striking morphological changes occur during the terminal stages of epidermal differentiation, such as a loss of major cellular organelles, the aggregation of keratin filaments and the formation of the cell envelope. A number of proteins are subjected to various post-translational modifications, including disulfide-bonding, isopeptide cross-linking [14], [15]. A number of proteins have been shown to be modified by PADs during the terminal stages of epidermal differentiation [16], [17]. They include keratins K1 and K10, filaggrin and trichohyalin [17]. Deimination of the keratin fibers/filaggrin complex results in the degradation of the latter to form a very concentrated pool of free amino acids which allows the cornified layer to retain water against the desiccating action of the environment [15]. Otherwise, deimination of trichohyalin facilitates its association to keratins in hair follicles [18], [19]. Similarly, deimination causes the assembly of a globular S100A3 homotetramer for hair cuticle barrier formation [5]. A 70-kD nuclear protein was found to be deiminated in keratinocytes culture, this being associated with apoptotic events of the cells [20]. Furthermore, deimination levels of proteins have been found to change during mouse skin development [21]. Recently, it was demonstrated that deiminated proteins were orderly formed in different layers of embryonic epidermis of human [22]. The presence of deiminated proteins mainly in the stratum corneum already suggested a function for deimination during terminal differentiation of keratinocytes. Altogether, the known targets of PADs in the skin are cytoskeletal and cytoskeleton-associated proteins, crucial components involved in forming rigid structures and keeping moisturizing for human skin. Deimination also has been associated with some cutaneous diseases. For example, an abnormally decreased level of deiminated keratin K1 has been reported in the involved areas of the epidermis of psoriatic patients [23]. Similarly, in bullous congenital ichthyosiform erythroderma (BCIE) a decrease in deiminated K1 has been found [23]. To sum up, these studies suggest important roles of PADs in human epidermal keratinization and morphogenesis. Since in human epidermis, the three PAD isoforms have different substrate specificities, investigating the mechanisms of regulation of the three enzymes may provide new insight into the etiology of the diseases and may contribute to the understanding of their involvement in the tissue physiology. 2. Transcriptional regulation of PADI1, 2 and 3 Despite the importance of PADs in skin homeostasis and human cutaneous diseases, relatively little is known regarding the regulation of their expression in human epidermal keratinocytes. In the following, we review what is known about the transcriptional regulation of PADI1–3 expression and highlight some significant features. 2.1. Organization of PADI1–3 promoter In order to investigate the regulatory elements involved, 5′-flanking regions of PADI1, PADI2 and PADI3 were cloned for the characterization of their proximal promoter. The transcriptional start sites of PADI1, PADI2 and PADI3 were 84, 80 and 41bp, respectively, upstream of the translation initiation codon (ATG), as shown by RNase protection analysis [24], [25], [26]. These data also correspond to the 5′-end sequence of PADI1–3 mRNAs that was determined by the 5′-RACE method [11], [12], [13]. Using normal human epidermal keratinocytes (NHEK) transfected with various deletion fragments of the 5′-upstream region of PADI1, 2 and 3 genes coupled to the luciferase reporter gene, we have shown that about 195, 132 and 129bp, respectively, upstream from their transcription start site are sufficient for an effective transcription (Fig. 4). Although PADI1, 2 and 3 share significant similarities in their coding nucleotide sequences, the sequence of their minimal promoter are poorly identical, thus the mechanisms responsible for the regulation of their expression seem to diverge. The minimal promoter of PADI1 reveals one putative specificity protein 1 (Sp1)-, four putative myeloid zinc finger 1 (MZF1)-binding motifs and a classic TATA box, by in silico analysis. Further comparison of about 200 nt regions upstream of the transcription initiation site of PADI1 and Padi1, the mouse orthologous gene, revealed extensive identities including these conserved cis-elements (Fig. 4A). Moreover, mutations of either the putative MZF1- or Sp1-binding sites markedly reduce PADI1 promoter activity. Based on these findings, it was suspected these conserve cis-elements function as key regulators for the basal expression of PADI1 gene in mammalian tissues. The PADI2 core promoter was shown to lack both a TATA box and a canonical CAAT box, but to contain some other typical eukaryotic promoter elements, including a Cap site and a high G+C content in the −150 to +200 region, and a CpG island which straddles exon 1 and extends into intron 1 and the flanking proximal promoter region [27]. The CpG island-containing PADI2 core promoter recently became a highlight because it was found hypomethylated in neurons of patients with multiple sclerosis. This may account for the increase of deimination and transcription of PADI2 in multiple sclerosis patient brain. The hypomethylated state of the PADI2 promoter seems to involve up-regulation of a DNA demethylase. So far, there is no information about the methylation state of the PADI2 promoter in dermatosis. The promoter of PADI3 is the most complicated among the three promoters; it contains a TATA-, two CCAAT- and two GC-boxes. Interestingly, the core nucleotide sequence of the CCAAT box-1, at nucleotides −126 to −122 of human PADI3, corresponds to a CCAGT sequence in mouse Padi3 (Fig. 4C). As a substitute, a putative CCAAT box-1′ sequence might be inserted into mouse Padi3 in the opposite direction (−117 to −121). As known as the function of the cis-element regardless of the direction of and distance from the promoter [28], it was deduced that all of these cis-elements, highly conserved in human and mouse, are indispensable for PAD3 gene expression. 2.2. Transfactor-binding mediated regulation Initial cloning and characterization of the PADI1–3 promoters has revealed several potential cis-elements for a number of distinct transcription factors. Further studies have indicated that these potential transcription factor binding sites identified in silico are functional in vivo and/or in vitro. Although the whole transcriptional system is not fully understand, in this section we will summarize the properties of the distinct transcription factors known to be involved in the transcriptional regulation of PADI1–3 so far (Fig. 5). In the case of PADI1, chromatin immunoprecipitation (ChIP) assays have demonstrated that MZF1 and Sp1/Sp3 bind to its promoter region in vivo. Furthermore, MZF1 or Sp1, but not Sp3, small interfering RNAs (siRNA) have effectively diminished the PADI1 expression in NHEK cultured in both low- and high-calcium containing medium. In addition, it also has been found that the expression of MZF1 and PAD1 increases synchronously during epidermal keratinocyte differentiation in vivo. Noteworthy, it has been found that two out of the four MZF1 binding sites are clearly the most important in response to high Ca2+ treatment, especially the most proximal to the TATA box. These observations suggested that the two sites might be critical as two main binding sites of MZF1. However, we cannot exclude a role of the other two MZF1 sites in the adequate expression of PADI1. It could be that MZF1 binding to these two latter sites may be weaker due to the binding of and blocking by Sp1. These data indicate that MZF1 and Sp1/Sp3 binding to the promoter region drive the PADI1 gene expression in NHEK. Although it lacks canonical TATA and CAAT boxes, the minimal promoter region of PADI2 contains some typical eukaryotic promoter elements, including four canonical GC boxes. We have shown their marked involvement in the transcription regulation of PADI2. Using electrophoretic mobility-shift assay (EMSA) and super-shift analyses, we have demonstrated that both Sp1 and Sp3 actually bind to the GC boxes. Moreover, since the GC boxes in the PADI2 promoter are overlapping or tightly clustered, the Sp proteins may interact with each other and display cooperative binding in regulating the gene. The ratio of Sp1/Sp3 bounded to the GC boxes of the PADI2 minimal promoter seems to parallel its transcriptional activity, i.e. higher the expression was detected by reverse transcription-PCR, higher was the relative importance of Sp1–DNA complexes observed in EMSA experiments. This was particularly evident for the two GC boxes closed to each other and located near the transcription start site. Altogether, consistent with similar results obtained for PADI1 and PADI3, the Sp1/Sp3 cooperation may provide an essential mechanism to control the transcription of PADI2 in NHEK [24]. PADI3 promoter that was found as few as 129bp upstream of the transcription initiation site has two CCAAT boxes, two GC boxes and a typical TATA box [25]. EMSA and ChIP assays have revealed that nuclear factor Y (NF-Y) present in keratinocyte extracts actually bind the two CCAAT boxes, while Sp1/Sp3 bind the two GC boxes both in vitro and in vivo. Either deletion or site-directed mutagenesis of one of the CCAAT or GC boxes dramatically decreases the promoter activity [29], [30], [31], [32], [33], [34]. Furthermore, Sp1 or NF-YA (one of the three subunits of NF-Y) small interfering RNAs effectively diminished PADI3 gene expression in NHEK cultured in both low- and high-calcium medium [25]. Therefore, both Sp1 and NF-Y are necessary for the expression of PADI3. They may form a heteromeric complex since a physical interaction between Sp1 and NF-Y has already been demonstrated [35], [36]. NF-Y and Sp1 are known to interact with the TATA-box-binding protein (TBP); the latter recognizes the TATA box and associates with TFIID for the initiation of gene transcription [37]. Moreover, the level of NF-Y is known to vary in different cell types or growth conditions and its DNA-binding properties are influenced by the intracellular calcium concentration [38], [39], [40]. We therefore assume that the level of intracellular calcium in NHEK regulates NF-Y binding to the PADI3 promoter region, and, together with Sp1/Sp3 binding, participates to the regulation of PADI3 gene expression. In the transcriptional regulation of PADI1, 2 and 3 in NHEK, Sp1/Sp3 is a common basic transcriptional factor. It seems also to be involved in the regulation of PADI4 in MCF-7 cells [41]. Sp-family of ubiquitous transcription activators, has been shown to regulate the constitutive expression of a considerable number of genes, and to take part in virtually all facets of cellular functions, including proliferation, apoptosis and differentiation [42]. Among the member of this family, Sp1 and Sp3 have been extensively characterized and are known to be co-expressed in several tissues/cell types and to interact with an identical consensus sequence [42], [43], [44]. Furthermore, Sp3 expression can either activate or repress a promoter activity, depending on the promoter and the type of cell [45], [46], [47]. Especially in human epidermis, Sp1 and Sp3 are involved in the regulation of genes involved in the keratinocyte differentiation program, including the genes encoding transglutaminase 1 and 3, loricrin, involucrin, keratin K5, Np63, profilaggrin and ATP2C1 [43]. All these results suggest that the ratio of Sp1 and Sp3 bound to the promoter of PADI genes is responsible for the induced expression of PAD1–3 in the upper keratinocyte layers of the epidermis. Indeed, the calcium gradient observed in the tissue is known to be involved in gene activation during keratinocyte differentiation [48]. However, reduction of Sp3 expression using specific siRNA has not significantly influenced the level of basal and Ca2+-enhanced PADI1 and PADI3 gene expression. Thereby, it is possible that the absence of Sp3 could be compensate by Sp1 but not the reverse, or that the remaining amount of Sp3 after siRNA treatments is still sufficient to regulate the transcription or that other transcription factors are involved. MZF1 binds the minimal promoter region of PADI1 and this transcription factor of the Krüppel family may account for the differentiation-specific expression of PADI1. MZF1 binding sites have not been identified in the promoter region of PADI2 and 3 [24], [25], [26]. MZF1 plays a key role in the hematopoietic development from embryonic stem cells, the early stages of myeloid cell differentiation, and in the granulopoiesis [49], [50]. Recently, MZF1 was found in transcriptional regulation of keratinocytes that probably acts as an activator of the basic transcriptional activity during cell proliferation, which in response to initiate extracellular Ca2+ signaling cascades that lead to promote PADI1 expression during cell early differentiation [24]. NF-Y, a trimeric, CCAAT-binding transcriptional activator has been until recently considered as a prototypical promoter transcription factor. However, some recent reports have shown that NF-Y induces DNA compaction. This in turn may facilitate promoter–enhancer interactions that are known to be critical for the regulation of gene expression [38]. 2.3. Involvement of calcium Calcium ion is not only the indispensable factor in the environment of deimination reaction, but is also considered as a major regulator of PADI genes at the transcriptional level. Similarly to the increased detection of PAD1–3 in the epidermis with the course of differentiation [7], the expression of PADI1–3 mRNAs is enhanced about two fold in NHEK cultured in 1.2mM calcium (differentiating conditions) as compared to 0.15mM (proliferating conditions). Ca2+ could control the binding of transcriptional factors to the promoters of the three genes. In particular, the level of Sp1 and/or Sp3 recruitment to the promoter and therefore the Sp1/Sp3 ratio have been shown to change according to the calcium concentration in the culture medium. Otherwise, the level of PAD1 gradually increases following stimulation of NHEK with a high-calcium concentration. In parallel the expression of MZF1 significantly enhances, with a maximum level after 96h, supporting the role of this transcription factor for up-regulating the PADI1 transcription. Regarding the PADI3 transcriptional regulation, it is known that NF-Y DNA-binding properties are influenced by intracellular Ca2+ concentrations [38], [39], [40]. Therefore we speculate that the level of intracellular Ca2+ in the cultured NHEK controls NF-Y binding to the PADI3 promoter region. In vivo, the increasing Ca2+ gradient known to exist from the basal layer to the stratum granulosum of the epidermis [4], is likely involved in the PADI1–3 gene regulation through the distribution/activity of transcription regulators, including Sp1/Sp3, MZF1 and NF-Y (Fig. 5). We also expect that local Ca2+ concentrations regulate the subcellular localization of the enzymes, and their activity. 3. Conclusions In conclusion, our research works on the transcriptional regulation of PADI1–3 genes in NHEK will help to understand the regulatory mechanisms involved in their tissue- and cell differentiation stage-specific expression, and more generally the control of the complex differentiation program of keratinocytes necessary for human skin homeostasis. Future researches will focus on long-rang and epigenetic controls of PADI1–3 genes. Recently, the importance of PADs in skin differentiation and skin disorders is becoming clearer and clearer. For example, decreased level of cytokeratin deimination was observed in the epidermis of patients with BCIE and psoriasis [23]. In addition, vitamin D which is effective in the treatment of psoriasis, increases the expression of PADI1–3 in keratinocytes grown in vitro [23]. 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[49]. [49]Perrotti D, Melotti P, Skorski T, Casella I, Peschle C, Calabretta B. Overexpression of the zinc finger protein MZF1 inhibits hematopoietic development from embryonic stem cells: correlation with negative regulation of CD34 and c-myb promoter activity. Mol Cell Biol. 1995;15:6075–6087. MEDLINE [50]. [50]Hromas R, Collins SJ, Hickstein D, Raskind W, Deaven LL, O’Hara P, et al. A retinoic acid-responsive human zinc finger gene, MZF-1, preferentially expressed in myeloid cells. J Biol Chem. 1991;266:14183–14187. MEDLINE  Shibo Ying graduated and received his MD degree from Department of Bioresource Science, Ibaraki University of Japan in 2008. Henceforth, he continued the research work in the same laboratory of Ibaraki University, Laboratory of Biochemistry & Molecular Biology, as a PhD student majored in Applied Life Science, United Graduate School, Tokyo University of Agriculture and Technology. He was awarded Japanese government scholarship and has been a member of Society for Investigative Dermatology (SID) since 2006. His present research interests are the transcriptional regulations of human PAD genes involved in epidermal keratinization and morphogenesis. In the past 5 years, he and his predecessors have succeeded to identify all the basal regulatory mechanisms of PADI1-4 gene expression. Currently, the related studies are still on the way.  Dr.Hidenari Takahara graduated and received his PhD degree from Tohoku University in 1978. He was an assistant professor in the Department of Biochemistry, Kinki University School of Medicine between 1978 and 1981. Then he moved to the Department of Applied Biological Resource Sciences, School of Agriculture, Ibaraki University. He was subsequently promoted to associate professor in 1988 and professor in 1996. He was a visiting associate professor at the Department of Dermatology, School of Medicine, University of California, San Francisco, USA (Prof. K. Fukuyama) from 1991 to 1992, and a visiting professor in the University P. Sabatier, Toulouse, France (Prof. G. Serre) from 2001 to 2002. In 1990, he received the award of Japan Society of Bioscience, Biotechnology, and Agrochemistry, regarding peptidylarginine deiminase. His research interests include basic research of protein deimination, especially biological functions and transcriptional regulation of peptidylarginine deiminases. a Department of Applied Biological Resource Sciences, School of Agriculture, Ibaraki University, Ami-machi, Inashiki-gun, Ibaraki 300-0393, Japan b Department of Dermatology, School of Medicine, Kinki University, Osaka 589-8511, Japan c CNRS-University of Toulouse III UMR 5165, Institut Fédératif de Recherche 30 (INSERM, CNRS, CHU Toulouse-Purpan, Université Paul Sabatier), CHU Purpan TSA40031, 31059 Toulouse cedex 9, France  Corresponding author. Tel.: +81 29 888 8681; fax: +81 29 888 8681.
PII: S0923-1811(08)00308-3 doi:10.1016/j.jdermsci.2008.09.009 © 2008 Japanese Society for Investigative Dermatology. Published by Elsevier Inc. All rights reserved. | |
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