A common ancestor to the three p53 family members of human genes p53, p63, and p73 is first detected in the evolution of modern-day sea anemones, in which both structurally and functionally it acts to protect the germ line from genomic instabilities in response to stresses. This p63/p73 common ancestor gene is found in almost all invertebrates and first duplicates to produce a p53 gene and a p63/p73 ancestor in cartilaginous fish. Bony fish contain all three genes, p53, p63, and p73, and the functions of these three transcription factors diversify in the higher vertebrates. Thus, this gene family has preserved its structural features and functional activities for over one billion years of evolution.
The etiology of esophageal squamous cell carcinoma (ESCC) has been shown to be associated with genetic and certain environmental factors that produce DNA damage. Base excision repair (BER) genes are responsible for repair of DNA damage caused by reactive oxygen species and other electrophiles and therefore are good candidate susceptibility genes for ESCC. We first screened eight BER genes for new and potential functional polymorphisms by resequencing 27 DNA samples. We then identified and genotyped for important tagging single nucleotide polymorphisms (SNPs) in a case-control study of 419 patients with newly diagnosed esophageal cancer and 480 healthy controls by frequency matching on age and sex. The association between genotypes and ESCC risk was estimated by unconditional multivariate logistic regression analysis, and stepwise regression procedure was used for constructing the final logistic regression model. We identified 129 SNPs in the eight BER genes, including 18 SNPs that cause amino acid changes. In the final model, 4 SNPs, including 2 in the coding regions (ADPRT Val762Ala and MBD4 Glu346Lys) and others in noncoding regions (LIG3 A3704G and XRCC1 T-77C), remained as significant predictors for the risk of ESCC. The adjusted odd ratios were 1.25 [95% confidence interval (CI) 1.02-1.53] for the ADPRT 762Ala allele, 1.25 (95% CI 1.02-1.53) for the MBD4 346 Lys allele, 0.78 (95% CI 0.63-0.97) for the LIG3 3704G allele, and 1.38 (95% CI 1.01-1.89) for the XRCC1-77C allele. In addition, we observed a significant gene-gene interaction between XRCC1 Gln399Arg and ADPRT Val762Ala. The results suggest that the polymorphisms in five BER genes may be associated with the susceptibility to ESCC in a Chinese population.
Tumor suppressor p53 is crucial for embryonic implantation through transcriptional up-regulation of uterine leukemia inhibitory factor (LIF). This article reports that p53 and estrogen receptor α were activated in endometrial tissues during implantation to coordinately regulate LIF production. By using human p53 knockin (Hupki) mice carrying a single nucleotide polymorphism (SNP) at codon 72 (arginine/proline), the arginine allele was demonstrated to produce higher uterine LIF levels during implantation than the proline allele. In humans, the diversity of haplotypes of the p53 gene has decreased during evolution, because the arginine allele, existing in only a subset of haplotypes, is under positive selection. This observation is consistent with previous results showing that the proline allele is enriched in patients undergoing in vitro fertilization (IVF). Studies with p63- and p73-knockout mice have demonstrated the involvement of p63 and p73 in female reproduction and their roles in egg formation and apoptosis (p63) and spindle checkpoint (p73) in female mice. Here, the role of p63 and p73 in human reproduction was investigated. Selected alleles of SNPs in p63 and p73 genes were enriched in IVF patients. These findings demonstrate that the p53 family members are involved in several steps to regulate female reproduction in mice and humans.
BackgroundThe human CYP3A gene cluster codes for cytochrome P450 (CYP) subfamily enzymes that catalyze the metabolism of various exogenous and endogenous chemicals and is an obvious candidate for evolutionary and environmental genomic study. Functional variants in the CYP3A locus may have undergone a selective sweep in response to various environmental conditions.ObjectiveThe goal of this study was to profile the allelic structure across the human CYP3A locus and investigate natural selection on that locus.MethodsFrom the CYP3A locus spanning 231 kb, we resequenced 54 genomic DNA fragments (a total of 43,675 bases) spanning four genes (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) and two pseudogenes (CYP3AP1 and CYP3AP2), and randomly selected intergenic regions at the CYP3A locus in Africans (24 individuals), Caucasians (24 individuals), and Chinese (29 individuals). We comprehensively investigated the nucleotide diversity and haplotype structure and examined the possible role of natural selection in shaping the sequence variation throughout the gene cluster.ResultsNeutrality tests with Tajima’s D, Fu and Li’s D* and F*, and Fay and Wu’s H indicated possible roles of positive selection on the entire CYP3A locus in non-Africans. Sliding-window analyses of nucleotide diversity and frequency spectrum, as well as haplotype diversity and phylogenetically inferred haplotype structure, revealed that CYP3A4 and CYP3A7 had recently undergone or were undergoing a selective sweep in all three populations, whereas CYP3A43 and CYP3A5 were undergoing a selective sweep in non-Africans and Caucasians, respectively.ConclusionThe refined allelic architecture and selection spectrum for the human CYP3A locus highlight that evolutionary dynamics of molecular adaptation may underlie the phenotypic variation of the xenobiotic disposition system and varied predisposition to complex disorders in which xenobiotics play a role.
The G-3113A polymorphism is associated with decreased CYP1A2 activity, haplotype pairs 10 and 13 are responsible for high CYP1A2 activity, and haplotype pairs 5, 8, 9, 12, and 15 are responsible for low CYP1A2 activity in Chinese subjects.
As a central event in liver fibrogenesis, hepatic stellate cell (HSC) transdifferentiation involves loss of regulation by adipogenic transcription factors such as peroxisome proliferator-activated receptor g; (PPARg), which is epigenetically silenced during HSC activation. We hypothesized that JMJD1A, an H3K9 demethylase involved in adipogenic metabolism, could regulate PPARg. In human HSC cell line, rat primary HSCs, and carbontetrachlorideinduced mouse liver fibrogenesis model, we down-regulated the expression of JMJD1A using small interfering or short hairpin RNAs, and overexpressed its wild-type and mutant. We analyzed the effects of JMJD1A manipulation on the histone di-methyl-H3K9 (H3k9me2) status of PPARg gene and the expression of PPARg and fibrosis markers using chromatin immunoprecipitation, real-time quantitative RT-PCR and Western blot, and also investigated the in vitro and in vivo consequences on liver fibrosis and necrosis by Masson or hematoxylin-eosin staining, respectively. JMJD1A knockdown in HSCs correlated with reinforced H3K9me2 in the PPARg gene promoter, and its down-regulation in both mRNA and protein led to increased expression of fibrosis markers, which could be consistently rescued by JMJD1A overexpression. Jmjd1a knockdown in situ resulted in significantly increased expression of a-smooth muscle actin (P = 0.005) and Col1a (P = 0.036), strengthened production of collagens (P = 0.028), and remarkably enhanced necrosis (P = 0.007) 4 weeks after treatment. This study suggests JMJD1A as a novel epigenetic regulator that modulates HSC activation and liver fibrosis through targeting PPARg gene
BackgroundLiver fibrosis is a middle stage in the course of chronic Hepatitis B virus (HBV) infection, which will develop into cirrhosis and eventually hepatocellular carcinoma (HCC) if not treated at the early stage. Considering the limitations and patients' reluctance to undergo liver biopsy, a reliable, noninvasive diagnostic system to predict and assess treatment and prognosis of liver fibrosis is needed. The aim of this study was to identify biomarkers for early diagnosis of HBV related liver fibrosis.MethodPlasma samples from 7 healthy volunteers and 27 HBV infected patients with different stages of fibrosis were selected for 2-DIGE proteomic screening. One-way ANOVA analysis was used to assess differences in protein expression among all groups. The alteration was further confirmed by western blotting. Plasma levels of 25 serological variables in 42 healthy volunteers and 68 patients were measured to establish a decision tree for the detection of various stages fibrosis.ResultThe up-regulated proteins along with fibrosis progress included fibrinogen, collagen, macroglobulin, hemopexin, antitrypsin, prealbumin and thioredoxin peroxidase. The down-regulated proteins included haptoglobin, serotransferrin, CD5 antigen like protein, clusterin, apolipoprotein and leucine-rich alpha-2-glycoprotein. For the discrimination of milder stage fibrosis, the area under curve for Prx II was the highest. Four variables (PT, Pre, HA and Prx II) were selected from the 25 variables to construct the decision tree. In a training group, the correct prediction percentage for normal control, milder fibrosis, significant fibrosis and early cirrhosis was 100%, 88.9%, 95.2% and 100%, respectively, with an overall correct percent of 95.9%.ConclusionThis study showed that 2-D DIGE-based proteomic analysis of the plasma was helpful in screening for new plasma biomarkers for liver disease. The significant up-expression of Prx II could be used in the early diagnosis of HBV related liver fibrosis.
The aim of this study was to identify polymorphisms in the histamine N-methyltransferase (HNMT) gene in Chinese and to assess their relationship with HNMT activity. One hundred and ninety-two unrelated subjects were recruited. HNMT polymorphisms were screened by direct sequencing with purified polymerase chain reaction products comprising all six exons, plus splice junctions, as well as approximately 2 kb of the 5'-flanking region (5'-FR). Erythrocyte HNMT activity was previously measured by radiochemical microassay. A total of 11 single nucleotide polymorphisms (SNPs) were identified, among which six SNPs had variant allele frequencies greater than 5%. Of the six common SNPs, three (-1637T>C, -463T>C and -411C>T) were located in 5'-FR, one (314C>T) in coding exons, and two (939A>G and 1097A>T) in the 3'-untranslated region (3'-UTR). Most of these common SNPs were in linkage disequilibrium. Genotype-phenotype correlation analyses were performed for those common SNPs in 5'-FR and 3'-UTR. In males, no significant association was found between HNMT activity and these non-coding SNPs. However, in females, the -1637T>C or -463T>C tended to be associated with decreased HNMT activity, whereas the 939A>G or 1097A>T appeared to be correlated with increased enzymatic activity. HNMT polymorphisms differ considerably between Chinese and American. The common SNPs in 5'-FR (-1637T>C and -463T>C) and 3'-UTR (939A>G and 1097A>T) might conditionally regulate the activity of HNMT, or might be genetically linked to unknown mutation(s) underlying the HNMT phenotypic variance.
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