title: An integrated genetic-epigenetic analysis of schizophrenia: Evidence for co-localization of genetic associations and differential DNA methylation.

status: Public on Aug 01 2016

city: Exeter

first: Jonathan

last: Mill

address: RILD Building, RD&E Hospital

department: Medical School

institute: University of Exeter

summary: Abstract  Background: Schizophrenia is a severe, highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Insights into the functional complexity of the genome have focussed attention on the role of non-sequence-based genomic variation in health and disease. Although a better understanding of the molecular mechanisms underlying disease phenotypes is best achieved using an integrated functional genomics strategy, few studies have attempted to systematically integrate genetic and epigenetic epidemiological approaches.    Results: We performed a multi-stage epigenome-wide association study (EWAS), quantifying genome-wide patterns of DNA methylation in a total of 1,801 individuals from three independent sample cohorts. We identified multiple differentially methylated positions (DMPs) and region (DMRs) associated with schizophrenia, independently of important confounders such as smoking, with consistent effects across the three independent cohorts. We also show that polygenic burden for schizophrenia is associated with epigenetic variation at multiple loci across the genome, independently of loci implicated in the analysis of diagnosed schizophrenia. Finally, we show how DNA methylation quantitative trait loci (mQTL) analyses can be used to annotate the extended genomic regions nominated by genetic studies of schizophrenia, with Bayesian co-localization analyses highlighting potential regulatory variation causally involved in disease.     Conclusion: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological pipeline that can be used to inform EWAS analyses of other complex traits and diseases. We demonstrate the utility of using polygenic risk score (PRS) for identifying molecular variation associated with etiological variation, and mQTLs for refining the functional/regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.

overall_design: 847 whole blood derived DNA samples (414 schizophrenia cases and 433 controls)  representing phase 2 of our meta-analysis. Bisulfite converted DNA from these samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip v1.0.

first: Eilis

last: Hannon

first: Emma

last: Dempster

first: Joana

last: Viana

first: Joe

last: Burrage

first: Adam

last: Smith

first: Ruby

last: Macdonald

first: David

last: St Clair

first: Colette

last: Mustard

first: Gerome

last: Breen

first: Sebastian

last: Therman

first: Jaakko

last: Kaprio

first: Timothea

last: Toulopoulou

first: Hilleke

middle: E

last: Pol

first: Marc

last: Bohlken

first: Rene

last: Kahn

first: Igor

last: Nenadic

first: Christina

last: Hultman

first: Robin

last: Murray

last: Collier

first: Nick

last: Bass

first: Hugh

last: Gurling

first: Andrew

last: McQuillin

first: Leonard

last: Schalkwyk


title: DNA Methylation of African Americans from the Grady Trauma Project

status: Public on Sep 03 2015

city: Atlanta

first: Alicia

last: Smith

address: 101 Woodruff Circle

country: USA

institute: Emory University

type: Methylation profiling by genome tiling array

summary: Childhood and cumulative exposure to trauma increases an individual's lifetime risk for psychiatric and stress-related disorders.  This study evaluates DNA methylation in whole blood from African American participants, with the goal of identifying associaitons between peripheral DNA methylation and psychiatric symptoms.

overall_design: DNA methylation was assessed in whole blood from participants of the Grady Trauma Project.  Blood was collected in EDTA vacuum tubes prior to extraction.  DNA methylation was interrogated for each sample using the HumanMethylation450 BeadChip (Illumina).

first: Kerry

last: Ressler

first: Elisabeth

last: Binder

first: Varun

last: Kilaru


title: Cosplicing network analysis of mammalian brain RNA-Seq data using WGCNA and Mantel correlations

status: Public on Dec 01 2014

city: Portland

first: Priscila

last: Darakjian

state: OR

address: 3181 SW Sam Jackson Park Road, L470

department: Behavioral Neuroscience

institute: Oregon Health and Science University

type: Expression profiling by high throughput sequencing

summary: Gene network analysis aims to understand how large groups of genes coordinate their activity to support complex biological functions. Gene coexpression networks are constructed on the basis of coordinated change in expression levels. However, a majority of genes have multiple versions or isoforms, often with distinct functionality. Gene cosplicing networks aim to capture coordinated changes in either isoform levels or relative ratios for different genes, which in principle could happen even with constant overall expression levels. We developed a method of capturing coordinated changes in isoform production, based on correlated exon inclusion rates. Integrating these correlations transcriptome wide results in a cosplicing network. The genes deemed important in the cosplicing network (hubs) include long many-exon genes with essential neurological functionality and association with autism spectrum disorders. Importantly, the cosplicing patterns are found, albeit with alterations, across species (mouse, macaque and human) and brain regions (striatum and cortex).

overall_design: 60 samples of HSCC animals tested for catalepsy were analyzed: 28 females (13 non-responders, 15 responders),  32 males (17 non-responders, 15 responders).

first: Ovidiu

middle: D

last: Iancu

first: Denesa

last: Oberbeck

first: Shannon

last: McWeeney

first: Robert

last: Hitzemann


title: PPARδ activation in human myotubes increases mitochondrial fatty acid oxidative capacity and reduces glucose utilization by a switch in substrate preference.

status: Public on May 23 2014

city: Wageningen

first: Guido

last: Hooiveld

address: HELIX, Stippeneng 4

department: Div. Human Nutrition & Health

country: Netherlands

institute: Wageningen University

summary:
The role of peroxisome proliferator-activated receptor δ (PPARδ) activation on global gene expression and mitochondrial fuel utilization were investigated in human myotubes. Only 21 genes were up-regulated and 3 genes were down-regulated after activation by the PPARδ agonist GW501516. Pathway analysis showed up-regulated mitochondrial fatty acid oxidation, TCA cycle and cholesterol biosynthesis. GW501516 increased oleic acid oxidation and mitochondrial oxidative capacity by 2-fold. Glucose uptake and oxidation were reduced, but total substrate oxidation was not affected, indicating a fuel switch from glucose to fatty acid. Cholesterol biosynthesis was increased, but lipid biosynthesis and mitochondrial content were not affected. This study confirmed that the principal effect of PPARδ activation was to increase mitochondrial fatty acid oxidative capacity. Our results further suggest that PPARδ activation reduced glucose utilization through a switch in mitochondrial substrate preference by up-regulating pyruvate dehydrogenase kinase isozyme 4 and genes involved in lipid metabolism and fatty acid oxidation.

Keywords: Expression profiling by array

overall_design: Human myotubes from four donors were exposed to a PPARδ agonist or control for 96 h after which gene expression was profiled.

first: Yuan

middle: Z

last: Feng

first: Natasa

last: Nikolic

first: Siril

middle: S

last: Bakke

first: Mark

middle: V

last: Boekschoten

first: Sander

last: Kersten

first: Eili

middle: T

last: Kase

first: Arild

middle: C

last: Rustan

first: G

middle: H

last: Thoresen


title: Human OEhMSCs on Gelfoam or bioconditioned gelfoam

status: Public on Aug 22 2014

city: Temple

first: Carl

middle: A

last: Gregory

state: Texas

address: 5701 Airport Road

department: Molecular and Cellular Medicine

institute: Texas A&M Health Sciences Center

summary: Human osteogenically enhanced mesenchymal stem cells were cultured for 5 days on standard gelfoam or gelfoam coated with MSC-derived extracellular matrix

overall_design: To address whether mesenchymal stem cell derived extracellular matrix might stimulate the secretion of osteogenic factors by OEhMSCs, we seeded them onto standard gelfoam or ECM-coated gelfoam in vitro and cultured them under standard conditions. After 5 days, we performed transcriptome micro-array analysis to identify genes that were up-regulated >2-fold.

first: Joni

last: Ylostalo

first: Bret

last: Clough


title: Analysis of the effect of vascular endothelial growth factor on gene expression profile after focal cerebral ischemia in mouse

status: Public on Jun 23 2014

city: Nanjing

first: Li

last: Wu

state: Jiangsu

address: 305 East Zhongshan Road

country: China

institute: Jinling Hospital, Nanjing University School of Medicine

summary: To investigate the effect of vascular endothelial growth factor (VEGF) on gene expression profile after focal cerebral ischemia in mouse, we employed Agilent SurePrint G3 Mouse Gene Expression 8×60K Microarray as a platform to identify which genes influenced by VEGF in mouse after focal cerebral ischemia. Mice were randomized to sham group, in which mice underwent sham surgery; MCAO group, in which transient (90 min) middle cerebral artery occlusion (MCAO) model was performed and mice received vehicle (PBS, 0.01M, pH 7.4) intracerebroventricularly in the right lateral ventricle 3hr after reperfusion; VEGF group (n = 36), in which rhVEGF-A165 (10μg/ml, dissolved in 0.01M PBS) was injected into the right lateral ventricle 3hr after reperfusion. Mice were sacrificed at 24hr after reperfusion, brains removed and peri-infarct areas were used for microarray. Gene expression microarray was applied to investigate the differentially expressed genes among sham group, MCAO group and VEGF group. Expression of thirty-seven genes was confirmed in the same RNA samples by real-time PCR.

overall_design: Gene expression in sham group, MCAO group and VEGF group was measured at 24 hours after reperfusion. Three independent experiments were performed using different mice for each experiment.

first: Yongjun

last: Jiang


title: DNA methylation analysis and expression profiling during murine embryogenesis and in embryos deficient for DNMT3A or DNMT3B

status: Public on Nov 14 2014

city: Illkirch

first: Michael

last: Weber

address: 300 Bd Sebastien Brant

department: UMR7242 Biotechnology and Cell Signalling

country: France

institute: CNRS

type: Methylation profiling by high throughput sequencing

summary: We quantified the targets and kinetics of DNA methylation acquisition in mouse embryos, and determined the contribution of the de novo methyltransferases DNMT3A and DNMT3B to this process. We provide single-base maps of cytosine methylation by RRBS from the blastocysts to post-implantation stages and in embryos lacking DNMT3A or DNMT3B activity, and performed RNA-Seq in embryos lacking DNMT3B activity.

overall_design: We sequenced RRBS libraries prepared from genomic DNA isolated from embryos at consecutive stages of development between E3.5 and E11.5,and adult differentiated cells (sperm, liver). We performed RRBS on blastocysts at E3.5/E4.5, dissected epiblasts at E5.5/E6.5/E7/5, whole embryos at E8.5/E10.5 and limbs at E11.5. RRBS experiments in Dnmt3a-/- and Dnmt3b-/- embryos were performed in biological duplicates on individual embryos. We sequenced RNA-Seq libraries prepared from total RNAs of three WT and Dnmt3b-/- littermate embryos collected at E8.5.

first: Ghislain

last: Auclair

first: Sylvain

last: Guibert


title: A coherent approach for analysis of the Illumina HumanMethylation450 BeadChip improves data quality and performance in epigenome-wide association studies

status: Public on Jan 22 2015

city: London

first: Benjamin

last: Lehne

address: Medicine, Norfolk Place, St Mary's Campus

department: Epidemiology and Biostatistics

country: United Kingdom

institute: Imperial College London

summary: We developed a comprehensive analysis pipeline to conduct Epigenome-wide Association Studies (EWAS) using the Illumina Infinium HumanMethylation450 BeadChip, based on data from 2,664 individuals, and 36 samples measured in duplicate. We propose new approaches to quality control, data normalisation and batch correction through control-probe adjustment, and demonstrate that these improve data-quality. Using permutation testing we establish a null hypothesis for EWAS, show how it can be affected by correlation between individual methylation markers and present methods to restore statistical independence.

overall_design: Bisulfite-converted DNA for 2,664 human samples and 36 technical replicates were hybridised to the Illumina Infinium 450k Human Methylation Beadchip v1.2.

first: Alexander

last: Drong

first: Marie

last: Loh

first: Weihua

last: Zhang

first: William

middle: R

last: Scott

first: Sian

last: Tan

first: Uzma

last: Afzal

first: James

first: Marjo

last: Jarvelin

first: Paul

last: Elliott

middle: I

last: McCarthy

first: Jaspal

last: Kooner

first: John

last: Chambers


title: Age-associated Changes in Basal NF-κB Function in Human CD4+ T Lymphocytes via Dysregulation of PI3 Kinase (dataset 5)

status: Public on Jan 08 2015

city: Baltimore

first: Supriyo

last: De

state: Maryland

address: 251 Bayview Blvd

department: Laboratory of Genetics and Genomics

institute: NIA-IRP, NIH

summary: Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dysregulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation, gene expression mediated by the transcription factor NF-κB is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-κB -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-κB up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dysregulated basal NF-κB activity may contribute to the mild pro-inflammatory state of aging.

overall_design: Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized blood using Ficoll-Paque Plus density gradient centrifugation. CD4+ T cells were obtained by positive selection using anti-human CD4 microbeads. To test the effects of drug treatment, 5x10^6 CD4+ T cells were treated with varying concentrations of rapamycin and also LY 294002 in 3 ml of RPMI 1640 medium. Control cells were also created without any added drugs. Cells were incubated for 4h in 5% CO2 at both 37°C and 4°C. After incubation, cells were harvested and collected by centrifugation. Total cellular RNA was prepared using Qiagen RNeasy protocols. Labeling and amplification were done with the standard Illumina protocol and the biotin-labeled cRNA was hybridized to Illumina's HumanHT-12 V4.0 Expression BeadChip. The arrays were washed, blocked and the biotin-labeled cRNA was detected by staining with streptavidin-Cy3.

first: Arsun

last: Bektas

first: Yongqing

first: Elin

last: Lehrmann

last: Wood III

first: Kevin

middle: G

last: Becker

first: Karen

last: Madara

first: Luigi

last: Ferrucci

first: Ranjan

last: Sen


title: Methylation Profiling of Blood DNA from Healthy Children

status: Public on Feb 16 2015

first: Benjamin

last: Barwick

state: GA

address: 1365 Clifton Rd. NE WCI-C 4th Floor Benches 36-37

department: Hematology and Medical Oncology

summary:
Analysis of the DNA methylation level in peripheral blood leukocytes from healthy children using the Illumina HumanMethylation450 BeadChip
Groupings by family membership requested but not provided by submitter

overall_design: DNA methylation association study in healthy children

first: Reid

last: Alisch

first: Pankaj

last: Chopra

first: Stephen

last: Warren


title: Programming and inheritance of parental DNA methylomes in mammals

status: Public on May 12 2014

city: Beijing

first: Lu

last: Wang

email: share.luwang@gmail.com, liuj@big.ac.cn

address: No.1 Beichen West Road

institute: Beijing Institute of Genomics

summary: The reprogramming of parental methylomes is essential for embryonic development. In mammals, paternal 5-methylcytosines (5mCs) have been proposed to be actively converted to oxidized bases. These paternal oxidized bases and maternal 5mCs are believed to be passively diluted by cell divisions. By generating single-base resolution, allele-specific DNA methylomes from mouse gametes, early embryos, and primordial germ cell (PGC), as well as single-base-resolution maps of oxidized cytosine bases for early embryos, we report the existence of 5hmC and 5fC in both maternal and paternal genomes and find that 5mC or its oxidized derivatives, at the majority of demethylated CpGs, are converted to unmodified cytosines independent of passive dilution from gametes to four-cell embryos. Therefore, we conclude that paternal methylome and at least a significant proportion of maternal methylome go through active demethylation during embryonic development. Additionally, all the known imprinting control regions (ICRs) were classified into germ-line or somatic ICRs.

overall_design:
The cross of two mouse strains was performed using DBA/2J as the paternal strain and C57BL/6J as the maternal strain. The hybrid embryos were collected at 2-cell, 4-cell, ICM, E6.5, E7.5 stages. Female and male E13.5 PGC samples (B6; 129S4-Pou5f1tm2Jae/J) were collected from timed mating of C57BL/6J female mice.
MethylC-Seq: oocytes (C57BL/6J), sperm (DBA/2J), 2-cell embryos, 4-cell embryos, ICM, E6.5 embryos, E7.5 embryos, E13.5 female PGCs and E13.5 male PGCs.
TAB-Seq: 2-cell embryos.
fCAB-Seq: 2-cell embryos.
RNA-Seq: oocytes (C57BL/6J).

first: Jiang

last: Liu


title: Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis

status: Public on Jul 23 2014

city: New York

first: Jorge

last: Moscat

state: NY

address: 1188 York Avenue

department: Pathology and Laboratory Medicine

institute: WEILL CORNELL MEDICINE

summary: The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the tumor epithelium are poorly understood. The signaling adapter p62 has been implicated as a positive regulator of epithelial tumorigenesis; however, its role in the stroma is unknown. We show here that p62 levels are reduced in the stroma of several tumors. Also, orthotopic and organotypic studies demonstrate that the loss of p62 in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism. Inhibition of the pathway by p62 deficiency results in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through modulation of metabolism in the tumor stroma.

overall_design: C57BL6 syngeneic TRAMP-C2Re3 cells (5×10^4) were injected orthotopically into the prostate of WT (n=6) or p62 KO (n=6) mice (C57BL6 background) and tumor growth was assessed, followed by transcriptome profiling of the orthotopic tumors (n=12).

first: Tania

last: Valencia

first: Ji

middle: Y

last: Kim

first: Shadi

last: Abu-Baker

last: Moscat-Pardos

first: Christopher

last: Ahn

first: Miguel

last: Reina-Campos

first: Elias

last: Castilla

first: Christian

middle: M

last: Metallo

first: Maria

last: Diaz-Meco


title: The DNA methylomes of serous borderline tumours reveal subgroups with malignant-like or benign-like profiles

status: Public on Dec 31 2012

first: Wei

last: Dai

address: Du Cane Road

department: Sugery and Cancer

summary: Serous borderline tumours (SBOT) are a challenging group of ovarian tumours positioned between benign and malignant disease. We have profiled the DNA methylomes of 12 low grade serous carcinoma (LGSC), 19 SBOT and 16 benign serous tumours (BST) across 27,578 CpG sites to further characterise the epigenomic relationship between these subtypes of ovarian tumours.   Unsupervised hierarchical clustering of DNA methylation levels showed that LGSC differ distinctly from BST, however, not from SBOT. Gene ontology analysis of genes showing differential methylation at linked CpG sites between LGSC and BST revealed significant enrichment of gene groups associated with cell adhesion, cell-cell signalling and the extracellular region consistent with a more invasive phenotype of LGSC as compared to BST. Consensus clustering highlighted differences between SBOT methylomes and returned subgroups with malignant-like or benign-like methylation profiles. Furthermore, a two loci DNA methylation signature can distinguish between these SBOT subgroups with benign-like and malignant-like methylation characteristics.   Our findings indicate striking similarities between SBOT and LGSC methylomes which supports a common origin and the view that LGSC may arise from SBOT. A subgroup of SBOT can be classified into tumours with a benign-like or a malignant-like methylation profile which may help in identifying tumours more likely to progress into LGSC.

overall_design: Array-based methylation profiling was performed using the Infinium HumanMethylation27 BeadChip in 12 low grade serous carcinoma, 19 serous borderline tumours and 16 benign serous tumours. The reproducibility of the Infinium HumanMethylation27 BeadChips was evaluated using four biological replicates of the high grade serous ovarian cancer cell line PEO1. Differential methylation cutoff was estimated from four biological replicates by bootstrap resampling and set at Δβ ≥ 0.25 corresponding to a FDR ≤ 0.09.

first: Constanze

last: Zeller

first: Edward

last: Curry

first: Afshan

last: Siddiq

first: Andrew

last: Walley

first: Nahal

last: Masrour

first: Isidora

last: Kitsou-Mylona

first: Gail

last: Anderson

first: Sadaf

last: Ghaem-Maghami

first: Robert

last: Brown

first: Mona

last: El-Bahrawy


title: Xist RNA is a potent suppressor of hematologic cancer in mice.

status: Public on Feb 20 2013

city: Boston

first: Ruslan

last: Sadreyev

state: MA

address: 185 Cambridge St

institute: Harvard Medical School/ Mass General Hospital

summary:
X-chromosome aneuploidies have long been associated with human cancers, but causality has not been established. In mammals, X-chromosome inactivation (XCI) is triggered by Xist RNA to equalize gene expression between the sexes. Here we delete Xist in the blood compartment of mice and demonstrate that mutant females develop a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome (mixed MPN/MDS) with 100% penetrance. Significant disease components include primary myelofibrosis, leukemia, histiocytic sarcoma, and vasculitis. Xist-deficient hematopoietic stem cells (HSC) show aberrant maturation and age-dependent loss. Reconstitution experiments indicate that MPN/MDS and myelofibrosis are of hematopoietic rather than stromal origin. We propose that Xist loss results in X-reactivation and consequent genome-wide changes that lead to cancer, thereby causally linking the X-chromosome to cancer in mice.  Thus, Xist RNA is not only required to maintain XCI but also suppresses cancer in vivo.
We carried out expression profiling in hematopoietic cells isolated from Xist-deficient female mice before disease (2 months old) and during myeloprolifeative neoplasm/myelodysplastic syndrome (MPN/MDS) and chronic myelomonocytic leukemia (CMML)-like disease (6 and 12 months old) and compared profiles of purified bone marow HSCs (KLS+CD34-), splenic B-cells (B220+), myeloid cells (CD11b+), and erythroid cells (Ter119+) against those of corresponding cell types from age-matched wild-type female mice.

overall_design: We conditionally targeted Xist locus in the blood compartment of mice by crossing Xist2lox/2lox mice (129Sv/Jae; Csankovszki et al., 1999) with Vav.Cre mice (B6.Cg-Tg (Vav1-cre)A2Kio/J; Jackson Laboratory).  We used hematopoietic cells that were isolated from Xist-deficient and wild-type female progeny to analyze changes in gene expression due to loss of Xist.

first: Eda

last: Yildirim

first: James

last: Kirby

first: Diane

first: Francois

last: Mercier

first: David

last: Scadden

first: Jeannie

last: Lee


title: Formaldehyde-induced changes in microRNA signaling

status: Public on Jan 07 2014

city: Chapel Hill

first: Rebecca

middle: Catherine

last: Fry

address: 1213 MHRC

department: Environmental Sciences and Engineering

institute: UNC-Chapel Hill

type:
Expression profiling by array
Non-coding RNA profiling by array

summary: This SuperSeries is composed of the SubSeries listed below.

overall_design: Refer to individual Series


title: Molecular signatures of human iPSCs highlight sex differences and cancer genes

status: Public on Dec 03 2013

summary: We compared human female hiPSC lines (all derived from IMR-90 fibroblasts) that were XIST RNA-positive and XIST RNA-negative.  We also examined the gene expression patterns for 2 female hIPSCs (derived from different disease model fibroblasts) that were also negative for XIST RNA. hiPS 12D-1 is derived from Huntington's Disease patient and 6C-1 is derived from a Type I Diabetes Mellitus patient (Park et al Nature 2008).

overall_design: hiPSCs (undifferentiated) were cultured to confluency then RNA was isolated using TriZOL (MEFs were removed using trypsin).  cDNA was converted using NuGEN then hybridized to Affymetrix 3' arrays.

first: M

last: Anguera

first: J


title: Age-associated Changes in Basal NF-κB Function in Human CD4+ T Lymphocytes via Dysregulation of PI3 Kinase (dataset 3)

first: Supriyo

last: De

overall_design: Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized blood using Ficoll-Paque Plus density gradient centrifugation. CD4+ T cells were obtained by positive selection using anti-human CD4 microbeads. After incubation for 4hr at either 4 or 37 Degrees C, cells were harvested and collected by centrifugation. Total cellular RNA was prepared using Qiagen RNeasy protocols. Labeling and amplification were done with the standard Illumina protocol and the biotin-labeled cRNA was hybridized to Illumina's HumanHT-12 V3.0 Expression BeadChip. The arrays were washed, blocked and the biotin-labeled cRNA was detected by staining with streptavidin-Cy3.

first: Arsun

last: Bektas

first: Yongqing

last: Zhang

first: Elin

last: Lehrmann

first: William

last: Wood III

first: Kevin

last: Becker

first: Karen

last: Madara

first: Luigi

last: Ferrucci

first: Ranjan

last: Sen


title: Formaldehyde-induced changes in microRNA signaling [Affymetrix]

summary: In addition to gaining knowledge on in vivo miRNA responses to formaldehyde, we set out to relate these miRNA responses to transcriptional profiles modified by formaldehyde. Rats were exposed by inhalation to either 0 or 2 ppm formaldehyde (6 hours/day) for 28 days. Genome-wide transcriptional profiles and associated signaling pathways were assessed within the nasal respiratory mucosa and circulating mononuclear white blood cells (WBC).

overall_design: Male Fischer rats received nose-only inhalation exposures of 2 ppm formaldehyde for 7 days or 28 days (6 hours/day). Control (unexposed) rats were placed in nose-only exposure tubes containing room air for the same duration. After the last exposure period, animals were euthanized. RNA were assessed from sampes collected from the nasal epithelium and circulating white blood cells. Genome-wide mRNA expression profiles were evaluated using microarrays.

first: Julia

last: Rager

first: Lisa

last: Smeester

first: Benjamin

last: Moeller

first: Melanie

last: Doyle-Eisele

first: James

last: Swenberg


title: Blood DNA methylation profiles in a Dutch population

status: Public on Oct 19 2012

city: Los Angeles

first: Steve

last: Horvath

state: CA

address: 695 Charles E. Young Drive South, Box 708822

department: Human Genetics

institute: University of California, Los Angeles

summary: Genome wide DNA methylation profiling of whole blood in schizophrenia patients and healthy subjects of different ages. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 480,000 CpGs. Dataset included 62 schizophrenia patients and 33 healthy subjects from Dutch descent.

overall_design:
Bisulphite converted DNA from the 96 samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip. Publication: Steve Horvath, Yafeng Zhang, Peter Langfelder, René S. Kahn, Marco P.M. Boks, Kristel van Eijk, Leonard H. van den Berg, Roel A. Ophoff. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biology. Special Edition.
The raw data (non-normalized Unmethylated and Methylated signal intensities) are not available.

first: Roel

last: Ophoff


title: Spreading of X-chromosome inactivation via a hierarchy of defined Polycomb stations

status: Public on Nov 01 2012

first: Ruslan

last: Sadreyev

type: Genome binding/occupancy profiling by high throughput sequencing

summary: Binding of Polycomb repressive complex 2 (PRC2) and chromatin composition of the inactive X (Xi) before, during and after X chromosome inactivation reveal that spreading is driven by a combination of Xi-specific strong and moderate Ezh2 sites. Sequence context of these sites shows a moderate enrichment of SINEs and simple repeats. The general pattern of Ezh2 and H3K27me3 distribution over the chromosome reflect a graded concentration originating from strong Ezh2 sites, around which moderate sites are clustered, suggesting a hierarchy of Ezh2 sites govern spreading.

overall_design: ChIP-seq of Ezh2 and H3K27me3 as well as the three active marks H3K4me3, H3K36me3 and RNA-POLII-serine5 phosphorylation (RNA-polII-S5P) in female cell lines: undifferentiated embryonic stem (ES) cells (d0), differentiating ES cells (d7) and a transformed embryonic fibroblast cell line (MEF).

first: Stefan

middle: F

last: Pinter

first: Eda

last: Yildirim

first: Yesu

last: Jeon

first: Toshiro

middle: K

last: Ohsumi

first: Mark

last: Borowsky

first: Jeannie

last: Lee


title: EPIC-Italy at HuGeF

status: Public on Sep 20 2013

first: Gianluca

last: Campanella

address: Norfolk Place

summary:
This Series contains data from 845 participants (188 men and 657 women) in the EPIC-Italy cohort that was produced at the Human Genetics Foundation (HuGeF) in Turin, Italy.
At the last follow-up (2010), 424 participants remained cancer-free, 235 had developed primary breast cancer, 166 had developed primary colorectal cancer, and 20 had developed other primary cancers.
Anthropometric measurements, and dietary and lifestyle information obtained by questionnaire are also available.

overall_design: A total of 845 samples from the EPIC-Italy cohort were analyzed.

first: Silvia

last: Polidoro

first: Vittorio

last: Krogh

first: Domenico

last: Palli

first: Salvatore

last: Panico

first: Rosario

last: Tumino

first: Paolo

last: Vineis


title: DNA methylation dynamics of the human pre-implantation embryo

city: San Francisco

first: Michelle

last: Chan

institute: UCSF

summary: We present genome-scale maps of DNA methylation in early human development and perform comparative analysis to mouse that confirm a conserved global erasure of the paternal genome.  We find that while many global features of the early embryo are consistent between the two species, the target sequences in which DNA methylation is maintained are distinct. Repetitive elements show a broader range of class specific behaviors in the human embryo and a larger degree of methylation escape in human sperm.  We identify thousands of differentially methylated regions (DMRs) that are likely of maternal origin and found that these gamete contributed DMRs are far more species-specific than expected given the conservation of canonical imprint control regions (ICRs). Finally, we extended our studies to the derivation of new human embryonic stem cell (ESC) lines and found notable divergences in DNA methylation signatures from those found in the human embryo and different mouse ESC derivation conditions.

sample_organism:
Homo sapiens
Mus musculus

platform_organism:
Homo sapiens
Mus musculus

overall_design: Comparison of DNA methylation patterns in human early development, human ESC derivation and mouse ESC derivation

first: Zachary

last: Smith

first: Kathryn

last: Humm

first: Shila

last: Mekhoubad

first: Aviv

last: Regev

first: Kevin

last: Eggan

first: Alexander

last: Meissner


title: T cell-intrinsic MyD88 signaling in cognate immune response to intracellular parasite infection: crucial role for IL-18R

status: Public on Aug 20 2014

first: Bernardo

last: Reis

address: 1234 York Avenue

institute: Rockefeller University

summary: We compared gene expression between WT CD4+ (CD45.1) and Myd88-/- CD4+ (CD45.2) T cells from the spleen of infected mix bone marrow chimeras at day 14 of T. cruzi infection. The hypothesis studied in this experiment was that MyD88-/- CD4+ cells have suppressed Th1 differentiation potencial when compared to WT CD4+ T cells. The results indicate that CD4+ T cell-intrinsic MyD88 signaling is necessary for sustaining a more robust Th1 differentiation program and increased expansion among WT CD4+ T cells, resultant of relative higher proliferation and lower apoptosis

overall_design: Total RNA obtained from isolated CD4+ T cells from the spleen of infected mix bone marrow chimeras at day 14 of T. cruzi infection.

first: Maria

last: Bellio

first: Helder

last: Nakaya

first: Alberto

last: Nóbrega


title: X-chromosome hyperactivation in mammals via nonlinear relationships between chromatin states and transcription

status: Public on Jan 06 2012

first: Ruslan

last: Sadreyev

summary: Dosage compensation in mammals occurs at two levels. In addition to balancing X-chromosome dosage between males and females via X-inactivation, mammals also balance dosage of Xs and autosomes. It has been proposed that X-autosome equalization occurs by upregulation of Xa (active X). To investigate the mechanism, we perform allele-specific ChIP-seq for chromatin epitopes and analyze RNA-seq data (SRA010053). The hypertranscribed Xa demonstrates enrichment of active chromatin marks relative to autosomes. We derive predictive models for relationships among Pol II, active mark densities and gene expression, and we suggest that Xa upregulation involves increased transcription initiation and elongation. Enrichment of active marks on Xa does not scale proportionally with transcription output, a disparity explained by nonlinear quantitative dependencies among active histone marks, Pol II occupancy and transcription. Notably, the trend of nonlinear upregulation also occurs on autosomes. Thus, Xa upregulation involves combined increases of active histone marks and Pol II occupancy, without invoking X-specific dependencies between chromatin states and transcription.

overall_design: Examination of 4 marks of active transcription (H3K4me3, H3K36me3, POL-II-S2P, POL-II-S5P) in a transformed female mouse embryonic fibroblast cell line (EY.T4).

first: Eda

last: Yildirim

first: Stefan

last: Pinter

first: Jeannie

last: Lee


title: DNA methylomes of Newborns and Nonagenarians

status: Public on Jun 13 2012

city: L'Hospitalet de Llobregat

first: Manel

last: Esteller

state: Barcelona

address: Hospital Duran i Reynals Av. Gran Via s/n km, 2.7

department: PEBC

country: Spain

institute: IDIBELL

summary: DNA methylation differences between Newborns and Nonagenarians

overall_design: The study aimed to compare the DNA methylation differences between newborns and nonagenarians using methylation array technology (450K, Illumina). The identified differently methylated CpG were further analyzed for their presence in diseases related to the aging phenotype (Werner and Progeria syndrome).

first: Holger

last: Heyn


title: Effects of chronic desipramine treatment on hippocampal transcriptome in mice differing in response to antidepressants

status: Public on Feb 26 2011

city: Berlin

first: Pawel

last: Lisowski

address: Hannoversche Str. 28

country: Germany

institute: Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association

summary: Analysis of chronic treatment with a tricyclic antidepressant (desipramine) at gene expression level in hippocampus of mice bred for  high (HA) or low (LA) swim stress-induced analgesia (SSIA).

overall_design: Total RNA obtained from isolated hippocampi of HA and LA mice subjected to 21 intraperitoneal injections of desipramine hydrochloride (7.5 mg/kg/day) compared to total RNA obtained from isolated hippocampi of HA and LA mice subjected to 21 intraperitoneal injections of saline.

first: Joanna

last: Goscik

first: Artur

last: Swiergiel


title: Expression data from primary breast tumors

status: Public on Jun 13 2009

city: Rotterdam

first: Marcel

last: Smid

address: Dr. Molewaterplein 50-60

department: Medical Oncology

institute: Erasmus Medical Centre

summary:
Brain metastasis is one of the most feared complications of cancer and the most common intracranial malignancy in adults. Its underlying mechanisms remain unknown. From breast cancer patients with metastatic disease we isolated cell populations that aggressively colonize the brain. Transcriptomic analysis of these cells yielded overlapping gene sets whose expression is selectively associated with brain metastasis. The expression of seventeen of these genes in primary breast tumors is associated with brain relapse in breast cancer patients. Some of these genes are also associated with metastasis to lung but not to liver, bone or lymph nodes, providing a molecular basis for the long-observed link between brain and lung metastasis. Among the functionally validated brain metastasis genes, the cyclooxigenase COX-2, the EGFR ligand HB-EGF, and the brain-specific  2-6 sialyltransferase ST6GALNAC5 mediate cancer cell passage through the blood-brain barrier. Other brain metastasis genes encode inflammatory factors and brain-specific proteolytic regulators, suggesting a multifaceted program for breast cancer colonization of the brain.

Keywords: Disease state comparison

overall_design: 204 primary tumors from breast cancer patients with known site of relapse were studied, focussing on brain relapse versus other relapse. Identified genes were validated in this cohort.


title: Genome wide FOXP3 binding sites in human cord blood derived CD4+CD25+ natural T regulatory cells (nTreg)

status: Public on Jun 22 2010

city: Adelaide

first: Stephen

middle: Martin

last: Pederson

state: SA

address: North Terrace

department: Biological Sciences

country: Australia

institute: University of Adelaide

type: Genome binding/occupancy profiling by genome tiling array

summary:
FOXP3 is essential for the stability and function of nTReg. We have characterised the FOXP3-dependent cis-regulatory network through a combination of whole genome ChIP-on-chip and transcriptional profiling of primary human nTreg cells . Human nTreg cells were isolated from cord blood and expanded ex vivo (day9). These analyses identified approximately 8,000 high quality FOXP3 binding sites the majority (85%) of which were located in proximity to annotated genes . Intersection of DNA binding data with gene expression profiles predicted 739 candidate target genes.
The supplementary bed file contains all 8305 high quality binding FOXP3 binding regions reported in the paper.

overall_design: Day9 expanded cord blood nTreg cells ChIPed with polyclonal rabbit anti-Foxp3 IgG (Novus Biochem) vs. Input chromatin

first: Tim

middle: J

last: Sadlon

first: Simon

last: Barry


title: A unique regulatory phase of DNA methylation in the early mammalian embryo

status: Public on Mar 28 2012

first: Michelle

last: Chan

summary: DNA methylation is highly dynamic during mammalian embryogenesis. It is broadly accepted that the paternal genome is actively depleted of global cytosine methylation at fertilization, followed by passive depletion that reaches a minimum at the blastocyst stage.  However, this model is based on limited data, and to date no base-resolution maps exist to support and refine it.  Here, we generated genome-scale DNA methylation maps in mouse gametes and through post-implantation embryogenesis.  We find that the oocyte already exhibits global hypomethylation, most prominently at specific subfamilies of LINE-1 and LTR-containing retro-elements, which are disparate between gametes and resolve to lower methylation values in zygote. Surprisingly, the oocyte contributes a unique set of Differentially Methylated Regions (DMRs), including many CpG Island promoter regions, that are maintained in the early embryo but are lost at the onset of embryonic specification and absent in somatic cells. In contrast, sperm contributed methylation includes retrotransposons that become completely methylated after the blastocyst stage. Our data provide a complete genome-scale, base-resolution timeline of DNA methylation in the pre-specified embryo, when this epigenetic modification is most dynamic and before returning to the canonical somatic pattern.

overall_design: Comparison of DNA methylation patterns in mouse gametes and through embryogenesis using Reduced Representation Bisulfite Sequencing (RRBS)

first: Zachary

middle: D

last: Smith

first: Tarjei

last: Mikkelsen

first: Hongcang

last: Gu

first: Andreas

last: Gnirke

first: Aviv

last: Regev

first: Alexander

last: Meissner


title: Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates

status: Public on Nov 21 2012

city: Seattle

first: Justin

last: Guinney

state: WA

address: 2606 E Roy St

institute: Sage Bionetworks

summary: Genome wide DNA methylation profiling of individuals across a large age range. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 450k CpGs from human whole blood.

overall_design: Bisulphite converted DNA from the 656 samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip

first: K

last: Zhang

first: T

last: Ideker


title: Differential DNA methylation in Rheumatoid arthritis

status: Public on Jan 21 2013

city: Shanghai

first: Yun

last: Liu

address: 130 Dong An Road

institute: Fudan University

summary:
Genome-wide DNA methylation level was studied to determine whether Rheumatoid arthritis patients (cases) has methylation differences comparing to normal controls in peripheral blood leukocytes (PBLs).
We used Illumina HumanMethylation450 BeadChip array to determine the genome-wide DNA methylation difference in PBLs from Rheumatoid arthritis patients (cases) and normal controls

overall_design: Bisulphite converted DNA from the Rheumatoid arthritis patients (cases) and normal controls were hybridized to the Illumina Illumina HumanMethylation450 BeadChip arrays

first: Andrew

middle: P

last: Feinberg


title: PCL Q3412.BG3 ChIP-chip

status: Public on Mar 12 2010

city: Toronto

first: DCC

last: modENCODE

state: Ontario

address: MaRS Centre, South Tower, 101 College Street, Suite 800

country: Canada

institute: Ontario Institute for Cancer Research

summary:
modENCODE_submission_948
This submission comes from a modENCODE project of Gary Karpen. For full list of modENCODE projects, see http://www.genome.gov/26524648
Project Goal: We aim to determe the locations of 125 chromosomal proteins and histone modifications across the Drosophila melanogaster genome. The proteins and modifications under study are involved in basic chromosomal functions such as DNA replication, gene expression, gene silencing, and inheritance. We will perform Chromatin ImmunoPrecipitation (ChIP) using genomic tiling arrays. We will initially assay localizations using chromatin from three cell lines and two embryonic stages, and will then extend the analysis of a subset of proteins to four additional animal tissues/stages.
For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf

Keywords: CHIP-chip

overall_design: EXPERIMENT TYPE: CHIP-chip. BIOLOGICAL SOURCE: Cell Line: ML-DmBG3-c2; Tissue: CNS-derived cell-line; Developmental Stage: third instar larval stage; Genotype: y v f mal; Sex: Unknown;  NUMBER OF REPLICATES: 4;  EXPERIMENTAL FACTORS: Cell Line ML-DmBG3-c2; Antibody PCL Q3412

first: Gary

last: Karpen

first: Sarah

last: Elgin

first: Andrey

last: Gortchakov

first: Greg

last: Shanower

first: Michael

last: Tolstorukov

first: Peter

last: Kharchenko

first: Mitzi

last: Kuroda

first: Vincenzo

last: Pirrotta

last: Park

first: Aki

last: Minoda

first: Nicole

last: Riddle

first: Yuri

last: Schwartz

first: Art

last: Alekseyenko

first: Cameron

last: Kennedy


title: Human Boolean Implication Network

status: Public on Aug 29 2018

city: La Jolla

first: Debashis

last: Sahoo

state: California

address: 9500 Gillman Drive

department: Pediatrics

institute: UCSD

type:
Expression profiling by array
Third-party reanalysis

summary: Numerous gene expression datasets from diverse human tissue samples have been already deposited in the public domain. There have been several attempts to do large scale meta-analyses of all of these datasets. Most of these analyses summarize pairwise gene expression relationships using correlation, or identify differentially expressed genes in two conditions.  We propose here a new large scale meta-analysis of all of the publicly available human datasets to identify Boolean logical relationships between genes. Boolean logic is a branch of mathematics that deals with two possible values. In the context of gene expression datasets we use qualitative high and low expression values. A strong logical relationship between genes emerges if at least one of the quadrants is sparsely populated.

relation:
SubSeries of: GSE119128
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overall_design: 25,955 published human microarray samples assayed on the GPL570 were re-analyzed. RMA was used to normalize the RAW CEL files all together.


title: A Clinically Relevant Gene Signature in Triple-Negative and Basal-Like Breast Cancer

status: Public on Sep 13 2011

city: Frankfurt

first: Thomas

last: Karn

address: Theodor-Stern-Kai 7

summary:
Current prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. Triple-negative breast cancers (TNBCs) are clinically heterogeneous, and prognostic markers and biology-based therapies are needed to better treat this disease.

We assembled Affymetrix gene expression data for 579 TNBCs and performed unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC. We used n=394 cases for discovery and n=185 cases for validation. Sixteen metagenes emerged that identified basal-like, apocrine and claudin-low molecular subtypes, or reflected various non-neoplastic cell populations including immune cells, blood, adipocytes, stroma, angiogenesis, and inflammation within the cancer. The expressions of these metagenes were correlated with survival and multivariate analysis was performed including routine clinical and pathological variables.

73% of TNBCs displayed basal-like molecular subtype that correlated with high histological grade and younger age. Survival of basal-like TNBC was not different from non-basal-like TNBC. High expression of immune cell metagenes was associated with good and high expression of inflammation and angiogenesis-related metagenes were associated with poor prognosis. A ratio of high B-cell and low IL-8 metagenes identified 32% of TNBC with good prognosis (HR 0.37, 95% CI 0.22-0.61; P<0.001) and was the only significant predictor in multivariate analysis including routine clincopathological variables.

We describe a ratio of high B-cell presence and low IL-8 activity as a powerful new prognostic marker for TNBC. Inhibition of the IL-8 pathway also represents an attractive novel therapeutic target for this disease.

overall_design:
Analysis of primary breast cancer biopsies from patients before treatment. No replicates. No control or reference samples are included.

The set of 579 TNBCs includes: (1) 67 new GEO Samples (GSM782523-GSM782589), (2) 489 re-analyzed GEO Samples (see 'Relation' links below), and (3) 23 re-analyzed ArrayExpress Samples.

Cohorts:
HH = University of Hamburg
FRA = University of Frankfurt, adjuvant chemotherapy
FRA-2 = University of Frankfurt, neoadjuvant chemotherapy
FRA-3 = University of Frankfurt, no adjuvant chemotherapy

Data processing of the 579 TNBC Samples:

MAS5 values were taken from GEO if available. For samples with no MAS5 values, CEL files were downloaded from GEO and the affy package from Bioconductor was used to generate MAS5 values. Next, MAS5 values corresponding only to the 22283 probesets from the U133A array were compiled. Subsequently, normalization of MAS5 data was performed using the command line version of the program CLUSTER 3.0 (Michael Eisen; updated by Michiel de Hoon; http://bonsai.hgc.jp/~mdehoon/software/cluster/command.txt).

The following three steps were performed in the following order:
1. log2 transformation of MAS5 values
2. median centering of arrays
3. magnitude normalization of arrays

These three steps correspond to the following commands:
cluster.com filename -l
cluster.com filename -ca m
cluster.com filename -na

The resulting dataset, which is linked below as a supplementary file, was used for the subsequent analyses.

first: Achim

last: Rody

first: Marcus

last: Schmidt

first: Volkmar

last: Müller

first: Uwe

last: Holtrich

first: Lajos

last: Pusztai

first: Manfred

last: Kaufmann