| peptidyl arginine deiminase 6 | OKDB#: 3709 |
| Symbols: | PADI6 | Species: | human | ||
| Synonyms: | hPADVI, PREMBL2 | Locus: | 1p36.13 in Homo sapiens |
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| General Comment |
Cytoplasmic lattice-like structure in oocytes contain PADI6. This structure is used for the storage of mRNAs, ribosomes, and the rest of the transcriptional machinery.
Chavanas S, et al reported comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6.
Peptidylarginine deiminases (PADs) convert arginine residues in proteins into citrullines. They are suspected to be involved in multiple sclerosis and rheumatoid arthritis pathophysiology, and they play a role in epidermis homeostasis and possibly in regulation of gene expression through histone modification. In humans, four isoforms encoded by the genes PADI1-4 are known so far. We here report the characterization and comparative analysis of the human (355 kb) and mouse (240 kb) PAD gene clusters on chromosomes 1p35-36 and 4E1, respectively. We characterized an as yet unknown human PADI6 gene, and cloned the corresponding cDNA encoding a 694-amino-acid protein. RT-PCR analysis showed a rather restricted pattern of tissue-specific expression, mainly in ovary, testis and peripheral blood leukocytes. Nucleotide substitution rates suggest that PADI genes are under purifying selection. Comparative analysis of the human and mouse sequences identified 251 conserved non-coding segments predominantly clustered within the promoter regions, the large (>10 kb) first intron of each of the genes PADI1-3, and an 8 kb PADI1-2 intergenic region. The presence of numerous transcription factor binding sites suggests the segments are putative regulatory elements. This study is the first description of the human PADI6 gene and encoded protein, and the first step towards a better understanding of the coordinated regulation of PADI gene expression.
NCBI Summary: This gene encodes a member of the peptidyl arginine deiminase family of enzymes, which catalyze the post-translational deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. The family members have distinct substrate specificities and tissue-specific expression patterns. This protein may play a role in cytoskeletal reorganization in the egg and in early embryo development. [provided by RefSeq, Sep 2012] |
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| General function |
Enzyme
, Epigenetic modifications |
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| Ovarian function | Oogenesis, Oocyte maturation, Early embryo development | ||||
| Comment | Potential role for PADI-mediated histone citrullination in preimplantation development. Kan R et al. ABSTRACT: BACKGROUND: The peptidylarginine deiminases (PADIs) convert positively charged arginine residues to neutrally charged citrulline on protein substrates in a process that is known as citrullination or deimination. Previous reports have documented roles for histone citrullination in chromatin remodeling and gene regulation in several tissue types, however, a potential role for histone citrullination in chromatin-based activities during early embryogenesis has not been investigated. RESULTS: In the present study, we tested by laser scanning confocal indirect immunofluorescence microscopy whether specific arginine residues on the histone H3 and H4 N-terminal tails (H4R3, H3R2 + 8 + 17, and H3R26) were citrullinated in mouse oocytes and reimplantation embryos. Results showed that all of the tested residues were deiminated with each site showing a unique localization pattern during early development. Given these findings, we next tested whether inhibition of PADI activity using the PADI-specific inhibitor, Clamidine, may affect embryonic development. We found that treatment of pronuclear stage zygotes with Cl-amidine reduces both histone H3 and H4 tail citrullination and also potently blocks early cleavage divisions in vitro. Additionally, we found that the Cl-amidine treatment reduces acetylation at histone H3K9, H3K18, and H4K5 while having no apparent effect on the repressive histone H3K9 dimethylation modification. Lastly, we found that treatment of zygotes with trichostatin A (TSA) to induce hyperacetylation also resulted in an increase in histone citrullination at H3R2 + 8 + 17. CONCLUSIONS: Given the observed effects of Cl-amidine on embryonic development and the well documented correlation between histone acetylation and transcriptional activation, our findings suggest that histone citrullination may play an important role in facilitating gene expression in early embryos by creating a chromatin environment that is permissive for histone acetylation. Phosphorylation-Dependent Interaction of Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein (YWHA) with PADI6 Following Oocyte Maturation in Mice. Snow AJ et al. Proteins in the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein family (YWHA, also known as 14-3-3) are involved in the regulation of many intracellular processes. We have examined the interaction of YWHA with peptidylarginine deiminase, type VI (PADI6), an abundant protein found in mammalian oocytes, eggs and early embryos. Peptidylarginine deiminases catalyze the posttranslational modification of peptidylarginine to citrulline. PADI6 is associated with oocyte cytoplasmic sheets and it has been shown that PADI6-deficient mice are infertile due to disruption of development beyond the two-cell stage. We found that PADI6 undergoes a dramatic developmental change in phosphorylation during oocyte maturation. This change in phosphorylation is linked to an interaction of PADI6 with YWHA in the mature egg. Recombinant glutathione S-transferase (GST) YWHA pull-down experiments and transgenic tandem affinity purification with liquid chromatography-mass spectrometry demonstrate a binding interaction between YWHA and PADI6 in mature eggs. YWHA proteins modulate or complement intracellular events involving phosphorylation dependent switching or protein modification. These results indicate that phosphorylation and/or YWHA binding may serve as a means of intracellular PADI6 regulation. Role for PADI6 and the cytoplasmic lattices in ribosomal storage in oocytes and translational control in the early mouse embryo. Yurttas P et al. The mechanisms that mediate the establishment of totipotency during the egg-to-embryo transition in mammals remain poorly understood. However, it is clear that unique factors stored in the oocyte cytoplasm are crucial for orchestrating this complex cellular transition. The oocyte cytoplasmic lattices (CPLs) have long been predicted to function as a storage form for the maternal contribution of ribosomes to the early embryo. We recently demonstrated that the CPLs cannot be visualized in Padi6(-/-) oocytes and that Padi6(-/-) embryos arrest at the two-cell stage. Here, we present evidence further supporting the association of ribosomes with the CPLs by demonstrating that the sedimentation properties of the small ribosomal subunit protein, S6, are dramatically altered in Padi6(-/-) oocytes. We also show that the abundance and localization of ribosomal components is dramatically affected in Padi6(-/-) two-cell embryos and that de novo protein synthesis is also dysregulated in these embryos. Finally, we demonstrate that embryonic genome activation (EGA) is defective in Padi6(-/-) two-cell embryos. These results suggest that, in mammals, ribosomal components are stored in the oocyte CPLs and are required for protein translation during early development. Peptidylarginine deiminase (PAD) is a mouse cortical granule protein that plays a role in preimplantation embryonic development Liu M, et al . BACKGROUND: While mammalian cortical granules are important in fertilization, their biochemical composition and functions are not fully understood. We previously showed that the ABL2 antibody, made against zona free mouse blastocysts, binds to a 75-kDa cortical granule protein (p75) present in a subpopulation of mouse cortical granules. The purpose of this study was to identify and characterize p75, examine its distribution in unfertilized oocytes and preimplantation embryos, and investigate its biological role in fertilization. RESULTS: To identify p75, the protein was immunoprecipitated from ovarian lysates with the ABL2 antibody and analyzed by tandem mass spectrometry (MS/MS). A partial amino acid sequence (VLIGGSFY) was obtained, searched against the NCBI nonredundant database using two independent programs, and matched to mouse peptidylarginine deiminase (PAD). When PAD antibody was used to probe western blots of p75, the antibody detected a single protein band with a molecular weight of 75 kDa, confirming our mass spectrometric identification of p75. Immunohistochemistry demonstrated that PAD was present in the cortical granules of unfertilized oocytes and was released from activated and in vivo fertilized oocytes. After its release, PAD was observed in the perivitelline space, and some PAD remained associated with the oolemma and blastomeres' plasma membranes as a peripheral membrane protein until the blastocyst stage of development. In vitro treatment of 2-cell embryos with the ABL2 antibody or a PAD specific antibody retarded preimplantation development, suggesting that cortical granule PAD plays a role after its release in preimplantation cleavage and early embryonic development. CONCLUSION: Our data showed that PAD is present in the cortical granules of mouse oocytes, is released extracellularly during the cortical reaction, and remains associated with the blastomeres' surfaces as a peripheral membrane protein until the blastocyst stage of development. Our in vitro study supports the idea that extracellular PAD functions in preimplantation development. Wright PW, et al 2003 reported that ePAD is an oocyte and early embryo-abundant peptidylarginine deiminase-like protein that localizes to egg cytoplasmic sheets. Selected for its high relative abundance, a protein spot of MW approximately 75 kDa, pI 5.5 was cored from a Coomassie-stained two-dimensional gel of proteins from 2850 zona-free metaphase II mouse eggs and analyzed by tandem mass spectrometry (TMS), and novel microsequences were identified that indicated a previously uncharacterized egg protein. A 2.4-kb cDNA was then amplified from a mouse ovarian adapter-ligated cDNA library by RACE-PCR, and a unique 2043-bp open reading frame was defined encoding a 681-amino-acid protein. Comparison of the deduced amino acid sequence with the nonredundant database demonstrated that the protein was approximately 40% identical to the calcium-dependent peptidylarginine deiminase (PAD) enzyme family. Northern blotting, RT-PCR, and in situ hybridization analyses indicated that the protein was abundantly expressed in the ovary, weakly expressed in the testis, and absent from other tissues. Based on the homology with PADs and its oocyte-abundant expression pattern, the protein was designated ePAD, for egg and embryo-abundant peptidylarginine deiminase-like protein. Anti-recombinant ePAD monospecific antibodies localized the molecule to the cytoplasm of oocytes in primordial, primary, secondary, and Graafian follicles in ovarian sections, while no other ovarian cell type was stained. ePAD was also expressed in the immature oocyte, mature egg, and through the blastocyst stage of embryonic development, where expression levels began to decrease. Immunoelectron microscopy localized ePAD to egg cytoplasmic sheets, a unique keratin-containing intermediate filament structure found only in mammalian eggs and in early embryos, and known to undergo reorganization at critical stages of development. Previous reports that PAD-mediated deimination of epithelial cell keratin results in cytoskeletal remodeling suggest a possible role for ePAD in cytoskeletal reorganization in the egg and early embryo. Potential Role for MATER in Cytoplasmic Lattice Formation in Murine Oocytes. Kim B et al. BACKGROUND: Mater and Padi6 are maternal effect genes that are first expressed during oocyte growth and are required for embryonic development beyond the two-cell stage in the mouse. We have recently found that PADI6 localizes to, and is required for the formation of, abundant fibrillar Triton X-100 (Triton) insoluble structures termed the oocyte cytoplasmic lattices (CPLs). Given their similar expression profiles and mutant mouse phenotypes, we have been testing the hypothesis that MATER also plays a role in CPL formation and/or function. METHODOLOGY/FINDINGS: Herein, we show that PADI6 and MATER co-localize throughout the oocyte cytoplasm following Triton extraction, suggesting that MATER co-localizes with PADI6 at the CPLs. Additionally, the solubility of PADI6 was dramatically increased in Mater(tm/tm) oocytes following Triton extraction, suggesting that MATER is involved in CPL nucleation. This prediction is supported by transmission electron microscopic analysis of Mater(+/+) and Mater(tm/tm) germinal vesicle stage oocytes which illustrated that volume fraction of CPLs was reduced by 90% in Mater(tm/tm) oocytes compared to Mater(+/+) oocytes. CONCLUSIONS: Taken together, these results suggest that, similar to PADI6, MATER is also required for CPL formation. Given that PADI6 and MATER are essential for female fertility, these results not only strengthen the hypothesis that the lattices play a critical role in mediating events during the oocyte-to-embryo transition but also increase our understanding of the molecular nature of the CPLs. | ||||
| Expression regulated by | Nobox, SP1 | ||||
| Comment | Characterization of the porcine peptidylarginine deiminase type VI gene (PADI6) promoter: Sp1 regulates basal transcription of the porcine PADI6. Xia X et al. (2015) It is a general consensus that oocyte quality is the key to embryo survival in pig reproduction. Thus, study on regulation of the ovary-associated gene is of great significance in pig breeding. Peptidylarginine deiminases (PADs) are a family of enzymes which catalyze the conversion of arginine to citrulline in proteins. The peptidylarginine deiminases type VI gene (PADI6) is mainly expressed in the ovary, and plays an important role in oocyte growth, fertilization and early embryo development. However, until now, little is known about its transcriptional regulation mechanism. Here, we firstly isolated and characterized the 5'-flanking region of porcine PADI6 gene. We determined the transcription start site using 5'-rapid amplification of cDNA ends (RACE) analysis, and identified the minimal promoter (-85/+68) that drove the basal expression of PADI6 by constructing various progressive deletions. Mutational analysis and electrophoretic mobility shift assays demonstrated Sp1 bound to the -56/-47 region of the PADI6 promoter. Furthermore, overexpression of Sp1 significantly increased the promoter activity and promoted PADI6 gene expression, and accordingly, inhibition of Sp1 expression with specific siRNA significantly reduced the promoter activity and suppressed the PADI6 expression. In addition, inhibition of Sp1 binding by Mithramycin A treatment reduced the transcriptional activity of PADI6 in a dose-dependent manner. Taken together, these data indicate that Sp1 is essential for the transcriptional regulation of PADI6.////////////////// The oocyte-specific transcription factor, Nobox, regulates the expression of Pad6, a peptidylarginine deiminase in the oocyte. Choi M et al. Nobox is an oocyte-specific transcriptional regulator. Nobox deficiency disrupts early folliculogenesis and the expression of oocyte-specific genes in mice. In the present study, we found that peptidylarginine deiminase 6 (Pad6) was downregulated in Nobox-null ovaries. Pad6 is preferentially expressed in oocytes and its transcript is detectable at embryonic day 16.5. In addition, we identified one Nobox DNA-binding element (NBE) within the mouse Pad6 promoter. The NBE includes a core sequence TAATTA. Sequence-specific binding of Nobox to the TAATTA motif was confirmed. Nobox overexpression augmented transcriptional activity of a luciferase reporter driven by mouse Pad6. Our findings indicate that Nobox is a critical regulator that orchestrates oocyte-specific genes such as Pad6 during folliculogenesis. | ||||
| Ovarian localization | Oocyte | ||||
| Comment | cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type VI Zhang J, et al . Peptidylarginine deiminase (PAD) catalyzes the post-translational modification of protein through the conversion of arginine to citrulline in the presence of calcium ions. Human, similar to rodents, has four isoforms of PAD (type I, II, III and IV/V), each of which is distinct in substrate specificity and tissue specific expression. In our large-scale sequencing project, we identified a new human PAD cDNA from a human fetal brain cDNA library. The putative protein encoded by this cDNA is designated hPADVI. Expression analysis of hPADVI showed that it is mainly expressed in adult human ovary and peripheral blood leukocytes. We conclude that hPADVI may be orthologous to mouse ePAD, basing on sequence comparison, chromosome localization and exon-intron structure analysis. PAD-mediated deimination of epithelial cell keratin resulting in cytoskeletal remodeling suggests a possible role for hPADVI in cytoskeletal reorganization in the egg and in early embryo development. This study describes a new important member of the human PAD family. Genomewide discovery and classification of candidate ovarian fertility genes in the mouse. Gallardo TD et al.. This is an oocyte-specific gene. | ||||
| Follicle stages | |||||
| Comment | Use of proteomics to identify highly abundant maternal factors that drive the egg to embryo transition. Yurttas P et al. As in vitro fertilization becomes an increasingly popular method for human reproduction, it is more critical than ever to understand the unique molecular composition of the mammalian oocyte. DNA microarray studies have successfully provided valuable information regarding the identity and dynamics of factors at the transcriptional level. However, the oocyte transcribes and stores a large amount of material that plays no obvious role in oogenesis but instead is required to regulate embryogenesis. Therefore, an accurate picture of the functional state of the oocyte requires both transcriptional profiling and proteomics. Here, we summarize our previous studies of the oocyte proteome and present new panels of oocyte proteins that we recently identified in screens of metaphase II-arrested mouse oocytes. Importantly, our studies indicate that several abundant oocyte proteins are not, as one might predict, ubiquitous housekeeping proteins, but instead are unique to the oocyte. Further, mouse studies indicate that a number of these factors arise from maternal effect genes (MEGs). One of the identified MEG proteins, PADI6, localizes to and is required for the formation of a poorly characterized, highly abundant cytoplasmic structure: the oocyte cytoplasmic lattices (CPLs). Additionally, a number of other MEG-derived abundant proteins identified in our proteomic screens have been found by others to localize to another unique oocyte feature: the Subcortical Maternal Complex (SCMC). Based on these observations, we put forth the hypothesis that the mammalian oocyte contains several unique storage structures, which we have named Maternal Effect Structures (MESs), that facilitate the oocyte to embryo transition (OET). | ||||
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| Mutations |
4 mutations
Species: mouse
Species: human
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | June 27, 2007, 1:34 p.m. | by: |
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| last update: | July 22, 2021, 3:20 p.m. | by: | hsueh email: |
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