The mutation spectrum of CYP1B1 among 104 primary congenital glaucoma patients of the genetically heterogeneous Iranian population was investigated by sequencing. We also determined intragenic single nucleotide polymorphism (SNP) haplotypes associated with the mutations and compared these with haplotypes of other populations. Finally, the frequency distribution of the haplotypes was compared among primary congenital glaucoma patients with and without CYP1B1 mutations and normal controls. Genotype classification of six high-frequency SNPs was performed using the PHASE 2.0 software. CYP1B1 mutations in the Iranian patients were very heterogeneous. Nineteen nonconservative mutations associated with disease, and 10 variations not associated with disease were identified. Ten mutations and three variations not associated with disease were novel. The 13 novel variations make a notable contribution to the ϳ70 known variations in the gene. CYP1B1 mutations were identified in 70% of the patients. The four most common mutations were G61E, R368H, R390H, and R469W, which together constituted 76.2% of the CYP1B1 mutated alleles found. Six unique core SNP haplotypes were identified, four of which were common to the patients with and without CYP1B1 mutations and controls studied.

SUCLA2 is one of several nuclear-encoded genes that can cause encephalomyopathy accompanied by mitochondrial DNA depletion. The disorder usually manifests in early childhood and leads to early death. The gene encodes one of the subunits of succinyl-CoA synthase, the enzyme that catalyzes the reversible conversion of substrates succinyl-CoA and ADP to products succinate and ATP in the tricarboxylic acid pathway. Thirty-two individuals harboring mutations in SUCLA2 have so far been reported, and five different mutations were observed among these individuals. Here we report identification of a novel mutation in SUCLA2 in two cousins affected with encephalomyopathy. The novel mutation causes p.Asp251Asn; the affected amino acid is likely positioned within the ATP-grasp domain of the encoded protein. As previously reported in other patients, we did not observe elevation of methylmalonic acid, the biochemical hallmark of patients with mutations in SUCLA2. We instead found elevated levels of succinylcarnitine.

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Methyl tert-butyl ether (MTBE) is widely used as gasoline oxygenate and octane number enhancer for more complete combustion in order to reduce the air pollution caused by motor vehicle exhaust. The possible adverse effects of MTBE on human health are of major public concern. However, information on the metabolism of MTBE in human tissues is scarce. The present study demonstrates that human cytochrome P450 2A6 is able to metabolize MTBE to tert-butyl alcohol (TBA), a major circulating metabolite and marker for exposure to MTBE. As CYP2A6 is known to be constitutively expressed in human livers, we infer that it may play a significant role in metabolism of gasoline ethers in liver tissue.

Endometriosis is major gynecological disease that affects over 10% of women worldwide and 30%-50% of these women have pelvic pain, abnormal uterine bleeding and infertility. The cause of endometriosis is unknown and there is no definite cure mainly because of our limited knowledge about its pathophysiology at the cellular and molecular levels. Therefore, demystifying the molecular mechanisms that underlie endometriosis is essential to develop advanced therapies for this disease. In this regard, HOX genes are remarkable because of their critical role in endometrial development and receptivity during implantation, which is attributed to their ability to mediate some of the sex steroid functions during the reproductive period. Access to the expression profiles of these genes would provide the necessary information to uncover new genes for endometriosis and assist with disease diagnosis and treatment. In this study we demonstrate an altered expression pattern for the HOX clusters (A-D) and their cofactors in both eutopic and ectopic conditions compared to control tissue biopsies. Remarkably, most of the intensive changes occurred in eutopic samples from endometriosis patients compared to control tissue biopsies. Pathway analysis revealed the involvement of differentially expressed genes in cancer that correlate with an association between endometriosis and cancer. Our results suggest critical roles for the HOX cluster and their cofactors in endometriosis pathophysiology.

BackgroundThe histones in the core of nucleosomes may be subject to covalent post-transcriptional modifications. These modifications are thought to correlate with and possibly affect various genomic functions, including transcription. Each modification may alone or in combination with other modifications influence or be influenced by transcription. We aimed to identify correlations between single modifications or combinations of modifications at specific nucleosome sized gene regions with transcription activity based on global histone modification and transcription data of human CD4+ T cells and three other human cell lines. Transcription activity was defined in a binary fashion as either on or off. The analysis was done using the Classification and Regression Tree (CART) data mining protocol, and the Multifactorial Dimensionality Reduction (MDR) method was performed to confirm the CART results. These powerful methods have not previously been used for analysis of histone modification data.ResultsWe showed that analysis of the single histone modification H2BK5ac at only four gene regions correctly predicted transcription activity status of over 75% of genes in CD4+ T-cells. The H2BK5ac modification status also had high power for prediction of gene transcription activity in the three other cell lines studied. The informative gene regions with the H2BK5ac modification were all positioned proximal to transcription initiation sites. The CART and MDR methods were appropriate tools for the analysis performed. In the study, we also developed a non-arbitrary protocol for binary classification of genes as transcriptionally active or inactive.ConclusionsThe importance of H2BK5ac modification with regards to transcription control has not previously been emphasized. Analysis of this single modification at only four nucleosome sized gene regions, all of which are at or proximal to transcription initiation, has high power for prediction of gene transcription activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1418-6) contains supplementary material, which is available to authorized users.

Study question Evolution of the ALX1 and PDHX genes expression and incorporation of H2BK5ac mark on the promoter of these genes in endometriotic tissues versus normal endometrium Summary answer Lower incorporation of H2BK5ac mark in ALX1 and PDHX promoters can because to downregulation of these genes in endometriotic tissues compared to normal endometrium. What is known already Endometriosis is considered as multifactorial disease affected by genetic, hormonal, and environmental factors. Recent evidences suggest the role of epigenetic mechanisms in this disease. Aristaless-like homeobox1 (ALX1) and Pyruvate Dehydrogenase Protein X (PDHX) genes are considered in this study. Studies show that upregulation of the ALX1 gene cause cell proliferation, migration, and invasion in cancer cells. PDHX is involved in cellular metabolism and acts as a tumor suppressor gene while maintaining normal homeostasis. It is Hypothesized that H2BK5ac which is known as a dynamic marker in promoter regions of active genes, may be involved in regulation of these gene expression. Study design, size, duration Ten eutopic and ectopic endometrium tissue, as well as ten normal endometrium, were collected. Ectopic biopsies were obtained using diagnostic laparoscopy, while the endometrial control samples and eutopic samples were collected via pipelle. Participants/materials, setting, methods RNA extraction and cDNA synthesis were done then the expression of ALX1 and PDHX genes evaluated by quantitative real-time PCR. Promoter regions of mentioned genes investigated for the incorporation of the epigenetic mark of H2BK5ac using Chromatin immunoprecipitation (ChIP) followed by real-time PCR. Data analysis performed using One-way ANOVA analysis (SPSS software) considered the significant level of P < 0.05. Main results and the role of chance Results showed that the expression of ALX1 was significantly decreased in eutopic endometrial samples compared to normal endometrium (p = 0.007). Also, there was a significant reduction in PDHX mRNA level in the eutopic and ectopic samples vs. normal endometrium (p = .017 and p =.021, respectively). The chromatin immunoprecipitation real-time PCR (ChIP PCR) analyses showed significantly lower incorporation of H2BK5ac epigenetic mark in ALX1 promoter in eutopic endometrial samples compared to normal endometrium (p = 0.007). Also, reduced incorporation of H2BK5ac at the PDHX promoter region was observed in both eutopic and ectopic endometrial samples compared to normal endometrium (p = 0.004 and p = 0.003, respectively). Limitations, reasons for caution The main limitation of our study is the low number of samples. Wider implications of the findings: Our results suggest that the marked lower levels of H2BK5ac in regulatory regions of ALX1and PDHX might lead to deregulation of these genes in tissue endometriotic samples. Trial registration number ‘not applicable’ for non-clinical trials

Background: Dysregulation of some HOX genes are important for the development of endometriosis. Endometriosis is a complex gynecologic disorder affecting as many as 10-15% of premenopausal women. The pathogenesis of endometriosis, as the presence of endometrium-like tissue outside the uterine cavity, is largely unknown. HOX genes, encoding homeodomain transcription factors, are dynamically expressed in endometrium, in which they are necessary for endometrial growth, differentiation, and implantation. Few investigations have been studied in this vast range of HOX genes with a network-based view. Network theory allows for a holistic understanding of the role of genes in diseases. The purpose of this study is to identify genes that cause this disease by focusing on the HOX family genes and their regulatory genes. Materials & Methods: Fifteen samples of eutopic and ectopic endometrium collected from patients in proliferation phase. PCR array was performed on sample groups for 84 HOX genes and their related genes. The statistical significance was determined by using t-test. PCA and Hierarchical clustering were carried out between different groups. The genes co-expression networks were constructed based on correlation between normalized gene expression data. Gene function was annotated based on Gene Ontology, the intervention in other diseases and expression in other tissues using the DAVID to clarify the function of important genes and the mechanism of endometriosis. Results: Among the analyzed genes, 30, 40 and 35 significantly differentially expressed genes were in eutopic, ectopic compared with normal and ectopic with eutopic samples, respectively. Twenty-eight genes had no significant alteration in none of the sample groups. Conclusion: The most significant genes and the genes in co-expression networks are effective genes in development, metabolic and neural processes. Another important point is that the some non-differently expressed genes in networks have many interactions with the significant genes, indicating that these non-significant genes also are likely contributed in endometriosis. Keywords: endometriosis, HOX, PCR-array, Co-expression network