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.
Chavanas
Stéphane
S
UMR 5165 CNRS-UPS, Epidermis differentiation and rheumatoid autoimmunity, Institut Fédératif de Recherche 30, Faculté de Médecine, (INSERM, CNRS, CHU Toulouse-Purpan, Université Paul Sabatier), 37 allées Jules Guesde, 31073 Toulouse cedex 7, France.
Méchin
Marie-Claire
MC
Takahara
Hidenari
H
Kawada
Akira
A
Nachat
Rachida
R
Serre
Guy
G
Simon
Michel
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000235:genetics; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D005091:Exons; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005796:Genes / Q000235:genetics; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D007438:Introns; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D010802:Phylogeny; D000080065:Protein-Arginine Deiminase Type 6; D000076342:Protein-Arginine Deiminases; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
D018076:DNA, Complementary; D007527:Isoenzymes; D004247:DNA; D006867:Hydrolases; C488263:PADI6 protein, human; D000080065:Protein-Arginine Deiminase Type 6; D000076342:Protein-Arginine Deiminases