Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6. 1508 20

Peptidylarginine deiminases (PADIs) are post-translational modification enzymes that catalyze the conversion of protein-bound arginine residues into citrulline residues in the presence of calcium ions. Among PADIs, PADI4 was identified as a rheumatoid arthritis-susceptibility gene (Suzuki et al. in Nat Genet 34:395, 2003). We identified a total of 87 single nucleotide polymorphisms (SNPs) in PADI1 and PADI3 gene loci. Following a comparison of our data with SNPs in the dbSNP database in the National Center for Biotechnology Information, 45 SNPs are considered to be novel: 33 were identified in the PADI1 gene locus and 12 in the PADI3 gene locus. We also identified two insertion-deletion polymorphisms in introns of the PADI1. The high-resolution map that we constructed in this study will serve as a useful resource for analyzing gene scans of complex diseases mapped to this local segment on chromosomal band 1p36.13.
 ...
PMID:Identification of 45 novel SNPs in the 83-kb region containing peptidylarginine deiminase types 1 and 3 loci on chromosomal band 1p36.13. 1515 Jun 96

Long-range cis elements are critical regulators of transcription, particularly for clustered paralogous genes. Such are the five PADI genes in 1p35-36 encoding peptidylarginine deiminases, which catalyze deimination, a Ca2+-dependent post-translational modification. Deimination has been implicated in the pathophysiology of severe human diseases such as multiple sclerosis and rheumatoid arthritis. The PADI genes present different expression patterns. PADI1-3 are expressed in the epidermis, with increased expression levels in the most differentiated keratinocytes. Previous studies on PADI proximal promoters failed to explain such specificity of expression. We identified a conserved intergenic sequence in the PADI locus (IG1), which may play a role in PADI transcriptional regulation. In this work, we identified two DNase I.hypersensitive sites located in IG1, PAD intergenic enhancer segment 1 (PIE-S1) and PIE-S2, which act in synergy as a bipartite enhancer of the PADI3 and probably PADI1 promoters in normal human epidermal keratinocytes differentiated by a high-calcium-containing medium (1.5 mM). PIE-S1 and PIE-S2 present all the hallmarks of transcriptional enhancers: orientation-independence, copy-number dependence and cell-type specificity. PIE-S1 and PIE-S2 comprise conserved putative binding sites for MIBP1/RFX1 and activator protein 1, respectively. Deletion mutant screening revealed that these sites are crucial for the enhancer activity. Furthermore, chromatin immunoprecipitation assays evidenced differential binding of JunD or c-Jun on the activator protein 1 site depending on the cell differentiation state. Our results reveal the molecular bases of the expression specificity of PADI1 and PADI3 during keratinocyte differentiation through a long-range enhancer and support a model of PADI gene regulation depending on c-Jun-JunD competition.
 ...
PMID:Long-range enhancer differentially regulated by c-Jun and JunD controls peptidylarginine deiminase-3 gene in keratinocytes. 1895 2