DNA methylation patterns associated with arsenicosis
ABSTRACT: DNA methylation patterns were analyzed in blood samples from humans unexposed or exposed to arsenic Using a state-of-the-art technique to map the methylomes of our study subjects, we identified a large interactome of hypermethylated genes that are enriched for their involvement in arsenic-associated diseases, such as cancer, heart disease, and diabetes. Notably, we have uncovered an arsenic-induced “suppressorome” - a complex of 17 known and putative tumor suppressors silenced in human cancers. This finding represents a pivotal clue in unravelling a possible epigenetic mode of arsenic induced disease. Overall design: DNA was extracted from 16 blood samples, 8 of which were from individuals showing signs of arsenicosis and 8 from individuals not showing signs of arsenicosis. CpG-methylated DNA was pulled down using a methyl binding domain protein. DNA samples were hybridized to Affymetrix Human Promoter 1.0R arrays, and chips were scanned using an Affymetrix scanner.
INSTRUMENT(S): [Hs_PromPR] Affymetrix Human Promoter 1.0R Array
Project description:DNA methylation patterns were analyzed in blood samples from humans unexposed or exposed to arsenic Using a state-of-the-art technique to map the methylomes of our study subjects, we identified a large interactome of hypermethylated genes that are enriched for their involvement in arsenic-associated diseases, such as cancer, heart disease, and diabetes. Notably, we have uncovered an arsenic-induced “suppressorome” - a complex of 17 known and putative tumor suppressors silenced in human cancers. This finding represents a pivotal clue in unravelling a possible epigenetic mode of arsenic induced disease. DNA was extracted from 16 blood samples, 8 of which were from individuals showing signs of arsenicosis and 8 from individuals not showing signs of arsenicosis. CpG-methylated DNA was pulled down using a methyl binding domain protein. DNA samples were hybridized to Affymetrix Human Promoter 1.0R arrays, and chips were scanned using an Affymetrix scanner.
Project description:Genome wide DNA methylation profiling of arsenic exposure and non-exposure population and patients with skin leisons. The Illumina Infinium HumanMethylation450 BeadChip (HM450K) was used to obtain DNA methylation profiles across approximately 450,000 CpGs in genomic DNA extracted from blood buffy coat samples. Samples included 66 arsenic exposure individuals, 35 non-exposure individuals and 18 arsenical skin lesion patients. Overall design: Bisulphite converted DNA from the 119 samples were hybridised to the Illumina Infinium HumanMethylation450 BeadChip (HM450K).
Project description:We used MethylCap-seq and RRBS to profile methylomes of purified human ovarian granulosa cells. Genomic DNA methylation patterns in ovarian granulosa cells were compared between two groups of women: i) oocyte donors (n=20) who were young (age 26 ± 2.2 years) and had robust response to ovarian stimulation during assisted reproductive technology (ART) (mean number of oocytes retrieved = 25); versus ii) poor responders (n=20) who were older (age 40 ± 2.3 years) and responded poorly to ovarian stimulation during ART (oocytes retrieved ≤4 and peak estradiol level ≤ 1000 pg/ml). The first group served as healthy control. The second group represented the majority of women in their early 40s who have the natural age-related decline of ovarian functions and therefore respond poorly to ovarian stimulation during ART. We compared DNA methylomes in ovarian granulosa cells from oocyte donors versus poor responders using two approaches: MethylCap-seq for broader genomic coverage, and RRBS for absolute quantification. Due to very limited amount of materials available from each poor responder, samples containing equal amounts of granulosa cell DNA were pooled from 10 individuals in each group. A second set of experiments pooling granulosa cell DNA samples from independent donor and poor responder groups (ten individuals each) was then performed. Overall design: mix 10 individuals into one sample; compare samples with age differences
Project description:There is strong epidemiologic evidence supporting that exposure to inorganic arsenic (iAs) exposure is responsible for a myriad of adverse health effects, including carcinogenesis of the bladder. This research aimed to identify novel epigenetic biomarkers of iAs exposure in target cells within a human population. Here we assessed genome-wide, gene-specific promoter DNA methylation levels assessed in exfoliated human bladder uroepithelial cells (BECs) in relationship to BEC iAs, monomethylated As (MMAs), dimethylated As (DMAs), and total As (tAs) concentrations from 46 individuals with varying levels of As exposure in Chihuahua, Mexico. These analyses identified genes with increased methylation associated with BEC iAs(III+V), MMAs(III+V), and tAs(III+V). These genes were enriched for signaling related to metabolic disease and cancer. Overall design: Individuals participating in the present study (n=46) represent a subcohort of a larger study (n=374) among residents of Chihuahua, Mexico, recruited between 2008 and 2013. Study participants were required to be at least 18 years of age and have at least 5 years of uninterrupted residency in the study area. Urine samples were collected and uroepithelial cell isolation occurred immediately. Exfoliated bladder uroepithelial cells (BECs) were isolated from freshly collected urine. As species in BECs were measured using hydride generation (HG) with preconcentration by cryotrapping (CT) and inductively coupled plasma-mass spectrometry (ICP-MS) (HG-CT-ICP-MS). DNA was extracted from the exfoliated BECs of 46 subjects using the QIAamp DNA Blood Mini Kit (Qiagen, Valenica, CA) according to manufacturer’s instruction. CpG-methylated DNA was isolated using the MethylMinerTM Methylated DNA Enrichment Kit (Invitrogen/Life Technologies, Grand Island, NY), amplified, and hybridized to Affymetrix Human Promoter 1.0R arrays.
Project description:A paired analysis of peripheral blood mononuclear cells (PBMCs) isolated before and after antiretroviral therapy (ART) from a robust number of HIV-infected patients (N=36). Results identify a total of 4,157 DEGs following ART in HIV-infected participants and the transition from a period of active virus replication before ART to one of viral suppression This study evaluated PBMC gene expression in cells from 36 (4 dropped from analysis) recently HIV-infected individuals to identify differentially expressed genes following 48 weeks of ART
Project description:Children conceived using Assisted Reproductive Technologies (ART) have a higher incidence of growth and birth defects, attributable in part to epigenetic perturbations. Both ART and germline defects associated with parental infertility could interfere with epigenetic reprogramming events in germ cells or early embryos. Mouse models indicate that the placenta is more susceptible to the induction of epigenetic abnormalities than the embryo, and thus the placental methylome may provide a sensitive indicator of ‘at risk’ conceptuses. Our goal was to use genome-wide profiling to examine the extent of epigenetic abnormalities in matched placentas from an ART/infertility group and control singleton pregnancies (n=44/group) from a human prospective longitudinal birth cohort, the 3D Study. Principal component analysis revealed a group of ART outliers. The ART outlier group was enriched for females and a subset of placentas showing loss of methylation of several imprinted genes including GNAS, SGCE, KCNQT1OT1 and BLCAP/NNAT. Within the ART group, placentas from pregnancies conceived with IVF/ICSI showed distinct epigenetic profiles as compared to those conceived with less invasive procedures (ovulation induction, intrauterine insemination). Male factor infertility and paternal age further differentiated the IVF/ICSI group, suggesting an interaction of infertility and techniques in perturbing the placental epigenome. Together, the results suggest that the human placenta is sensitive to the induction of epigenetic defects by ART and/or infertility, and we stress the importance of considering both sex and paternal factors and that some but not all ART conceptuses will be susceptible. Overall design: Placenta from ART smaples are compared to control samples, of note that all samples were collected from one ART center and over the same period of time. Controls and ART samples were matched for new born sex, term gestation and matcernal age. Furthermore, an analysis comparing ART subtypes (In-vio versus in-vitro) was also performed.
Project description:Talemi2014 - Arsenic toxicity and
detoxification mechanisms in yeast
The model implements arsenite (AsIII)
transport regulation, its distribution within main cellular AsIII
pools and detoxification. The intracellular As pools considered are
free AsIII (AsIIIin), protein-bound AsIII (AsIIIprot), glutathione
conjugated AsIII (AsGS3) and vacuolar sequestered AsIII (vAsGS3).
This model is described in the article:
Mathematical modelling of
arsenic transport, distribution and detoxification processes in
Talemi SR, Jacobson T, Garla V,
Navarrete C, Wagner A, Tamás MJ, Schaber J.
Mol. Microbiol. 2014 Jun; 92(6):
Arsenic has a dual role as causative and curative agent of
human disease. Therefore, there is considerable interest in
elucidating arsenic toxicity and detoxification mechanisms. By
an ensemble modelling approach, we identified a best
parsimonious mathematical model which recapitulates and
predicts intracellular arsenic dynamics for different
conditions and mutants, thereby providing novel insights into
arsenic toxicity and detoxification mechanisms in yeast, which
could partly be confirmed experimentally by dedicated
experiments. Specifically, our analyses suggest that: (i)
arsenic is mainly protein-bound during short-term (acute)
exposure, whereas glutathione-conjugated arsenic dominates
during long-term (chronic) exposure, (ii) arsenic is not stably
retained, but can leave the vacuole via an export mechanism,
and (iii) Fps1 is controlled by Hog1-dependent and
Hog1-independent mechanisms during arsenite stress. Our results
challenge glutathione depletion as a key mechanism for arsenic
toxicity and instead suggest that (iv) increased glutathione
biosynthesis protects the proteome against the damaging effects
of arsenic and that (v) widespread protein inactivation
contributes to the toxicity of this metalloid. Our work in
yeast may prove useful to elucidate similar mechanisms in
higher eukaryotes and have implications for the use of arsenic
in medical therapy.
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Project description:Total RNA was purified from keratinocytes isolated from FFPE arsenic-induced skin lesion samples collected from individuals exposed to high concentrations of arsenic exceeding 50 ppb in drinking water in Murshidibad district of West Bengal, India. Overall design: The ΔCt values of miRNAs measured from malignant were compared to those of premalignant lesions or ΔCt values malignant lesions (BCC &SCC) were also compared to
Project description:We apply RNA-seq to limited populations of Innate Lymphoid Cells type 2 and type 3 (ILC2s and ILC3s, respectively) in human individuals infected with acute HIV in the FRESH study. We measured the whole transcriptome of ILC2s and ILC3s in both untreated (n=2) and ART treated (n=2) individuals over the course of infection, in order to compare these populations at key points during infection, namely: viral detection, peak viremia, and weeks past peak viremia (6-7 weeks post detection). Lacking true biological replicates, HIV- patients in the same study (n=9) were used as replicates to conduct Differential Expression (DE) analysis between time points in both ILC2s and ILC3s on a patient by patient basis. In untreated patients, ILC2s and ILC3s differentially expressed genes associated with apoptosis and cell death between peak viremia and viral detection, while ART treated patients' ILC2s and ILC3s demonstrated a mitigated response. Comparing 6-7 weeks after detection with peak viremia revealed a relative decrease in genes associated in cell death in untreated patients, while ART treated patients showed varied responses where several DE genes were associated with immune response. Overall design: RNA-seq of two Innate Lymphoid Cell populations in 2 HIV+ untreated patients, 2 HIV+ ART treated patients, and 9 HIV- patients (control, replicates).