Papers by Youssef Idaghdour
Hyperglycemia is a major risk factor in the development of diabetic complications and promotes va... more Hyperglycemia is a major risk factor in the development of diabetic complications and promotes vascular complications through dysregulation of endothelial cell function. Various mechanisms have been proposed for endothelial cell dysregulation but the early transcriptomic alterations of endothelial cells under hyperglycemic conditions are not well documented. Here we use deep time-series RNA-seq profiling of human aortic endothelial cells (HAECs) following exposure to normal (NG) and high glucose (HG) conditions over a time course from baseline to 24 hours to identify the early and transient transcriptomic changes, alteration of molecular networks, and their temporal dynamics. The analysis revealed that the most significant pathway activation/inhibition events take place in the 1- to 4-hour transition and identified distinct clusters of genes that underlie a cascade of coordinated transcriptional events unique to HG conditions. Temporal co-expression and causal network analysis impli...
European Journal of Clinical Microbiology & Infectious Diseases, 2021
To understand the reasons of successful spread of carbapenem-resistant Klebsiella pneumoniae ST14... more To understand the reasons of successful spread of carbapenem-resistant Klebsiella pneumoniae ST14 (CRKP-ST14) in countries of the Arabian Peninsula, the resistome, capsular locus, carbapenemase carrying plasmid types, and core genome of isolates from the region were compared to global isolates. Thirty-nine CRKP-ST14 strains isolated from 13 hospitals in the United Arab Emirates, Bahrain, and Saudi Arabia were selected for whole genome sequencing on Illumina MiSeq platform based on the variety of carbapenemase genes carried and plasmids bearing these genes. Their resistome, capsular locus, and core genome MLST were compared to 173 CRKP-ST14 genomes available in public databases. The selected 39 CRKP-ST14 produced either NDM-1, OXA-48, OXA-162, OXA-232, KPC-2, or co-produced NDM-1 and an OXA-48-like carbapenemase. cgMLST revealed three clusters: 16 isolates from five UAE cities (C1), 11 isolates from three UAE cities and Bahrain (C2), and 5 isolates from Saudi Arabia (C3), respectivel...
Science Signaling, 2020
The mechanisms by which excessive fluoride causes defects in tooth enamel mineralization are reve... more The mechanisms by which excessive fluoride causes defects in tooth enamel mineralization are revealed.
Science Signaling, 2019
SOCE mediated by ORAI1 affects the metabolism, redox status, and function of enamel cells in teeth.
JCI insight, Jan 23, 2017
Loss-of-function mutations in stromal interaction molecule 1 (STIM1) impair the activation of Ca(... more Loss-of-function mutations in stromal interaction molecule 1 (STIM1) impair the activation of Ca(2+) release-activated Ca(2+) (CRAC) channels and store-operated Ca(2+) entry (SOCE), resulting in a disease syndrome called CRAC channelopathy that is characterized by severe dental enamel defects. The cause of these enamel defects has remained unclear given a lack of animal models. We generated Stim1/2(K14cre) mice to delete STIM1 and its homolog STIM2 in enamel cells. These mice showed impaired SOCE in enamel cells. Enamel in Stim1/2(K14cre) mice was hypomineralized with decreased Ca content, mechanically weak, and thinner. The morphology of SOCE-deficient ameloblasts was altered, showing loss of the typical ruffled border, resulting in mislocalized mitochondria. Global gene expression analysis of SOCE-deficient ameloblasts revealed strong dysregulation of several pathways. ER stress genes associated with the unfolded protein response were increased in Stim1/2-deficient cells, whereas ...
G3 (Bethesda, Md.), Aug 9, 2017
Expression QTL (eQTL) detection has emerged as an important tool for unraveling of the relationsh... more Expression QTL (eQTL) detection has emerged as an important tool for unraveling of the relationship between genetic risk factors and disease or clinical phenotypes. Most studies use single marker linear regression to discover primary signals, followed by sequential conditional modeling to detect secondary genetic variants affecting gene expression. However, this approach assumes that functional variants are sparsely distributed and that close linkage between them has little impact on estimation of their precise location and magnitude of effects. We describe a series of simulation studies designed to evaluate the impact of linkage disequilibrium on the fine-mapping of causal variants with typical eQTL effect sizes. In the presence of multi-site regulation, even though between 80% and 90% of modeled eSNPs associate with normally distributed traits, up to 10% of all secondary signals could be statistical artefacts, and at least 5% but up to one quarter of credible intervals of SNPs wit...
Frontiers in oncology, 2017
Epigenetic alterations play an important role in the development of acute myeloid leukemia (AML) ... more Epigenetic alterations play an important role in the development of acute myeloid leukemia (AML) by silencing of genes that suppress leukemogenesis and differentiation. One of the key epigenetic changes in AML is gene silencing by DNA methylation. The importance of this alteration is illustrated by the induction of remissions in AML by 5-aza-2'-deoxycytidine (5-AZA-CdR, decitabine), a potent inhibitor of DNA methylation. However, most patients induced into remission by 5-AZA-CdR will relapse, suggesting that a second agent should be sought to increase the efficacy of this epigenetic therapy. An interesting candidate for this purpose is 3-deazaneplanocin A (DZNep). This analog inhibits EZH2, a histone methyltransferase that trimethylates lysine 27 histone H3 (H3K27me3), a marker for gene silencing. This second epigenetic silencing mechanism also plays an important role in leukemogenesis as shown in preclinical studies where DZNep exhibits potent inhibition of colony formation by ...
PLOS ONE, 2016
Assuming type 1 and 2 error rates of 5 and 20%, respectively and 14 observations per measure (i.e... more Assuming type 1 and 2 error rates of 5 and 20%, respectively and 14 observations per measure (i.e. one measure/day for two weeks), a correlation between measures within subjects over time of 0.5, assuming 50% non-sphericity, would be satisfied with 18 subjects. This would be sufficient to detect an effect where 25% or more of the variance was attributable to periodicity; we believe that some of the 10% within and 20% between individual variations currently observed in studies of human metabolite profiles are due to the effects of long period rhythms. Cognizant of this, future research is likely reduce this variability. To provide context, this is considered a moderate effect size in situations where prior data are not available to estimate the potential size of these effects. This estimate is the minimal sample size that is most appropriate for the first sampling strategy. Animals, care, housing, and diets Animal care protocols and procedures were reviewed and approved by the University of Wisconsin-Madison Institutional Animal Care and Use Committee (IACUC). The approved protocol number was A01324-0-11-10. Animals were housed in a facility accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC) throughout the experimental procedures. Thirty-six crossbred (Landrace X Large White X Line 19, ~ 5 mo, 100 kg BW) female pigs (gilts) were divided into 2 groups for replicate trials (n=16 gilts, Trial 1; n=20 gilts, Trial 2). Trial 1 was completed during the period April 24 to May 12, 2011, and Trial 2 during the period of May 15 to June 2, 2012. Gilts were housed individually in pens (2.1 X 0.6 m) that prevented the gilt from turning around to facilitate sample collections. Room temperature and humidity measurements were recorded at 15 minute intervals and mediated throughout the trials. Lights were electronically controlled to provide a 12 h light/dark cycle with lights on at 06:00 and off at 18:00 each day. All emergency and stray-light sources were blocked. Red lights that provided <5 lux light were used to facilitate collections during the dark cycle. Gilts were fed either a corn-soybean meal control (Ctl) diet or an acidogenic diet (Acd) which was formulated as the Ctl diet plus 2.0% of an anionic salt. The anionic salt is a commercially available product, CAD-MATE, a blend of anionic salts consisting of ammonium sulfate, calcium sulfate, and magnesium chloride (Granco Minerals, Petersburg, VA). Diets were fed for an 18 d trial. Each Trial included a 3-d adjustment period and 14-d collection period. Continuous access to assigned dietary treatments and water were allowed throughout the adjustment and collection periods. Feed consumption was recorded daily. To identify possible effects of the two diets on metabolite levels, analysis of variance (ANOVA) was performed. The model specification was:
Clinical epigenetics, 2014
The silencing of tumor suppressor genes (TSGs) by aberrant DNA methylation occurs frequently in a... more The silencing of tumor suppressor genes (TSGs) by aberrant DNA methylation occurs frequently in acute myeloid leukemia (AML). This epigenetic alteration can be reversed by 5-aza-2'-deoxcytidine (decitabine, 5-AZA-CdR). Although 5-AZA-CdR can induce complete remissions in patients with AML, most patients relapse. The effectiveness of this therapy may be limited by the inability of 5-AZA-CdR to reactivate all TSGs due to their silencing by other epigenetic mechanisms such as histone methylation or chromatin compaction. EZH2, a subunit of the polycomb repressive complex 2, catalyzes the methylation of histone H3 lysine 27 (H3K27) to H3K27me3. 3-Deazaneplanocin-A (DZNep), an inhibitor of methionine metabolism, can reactivate genes silenced by H3K27me3 by its inhibition of EZH2. In a previous report, we observed that 5-AZA-CdR, in combination with DZNep, shows synergistic antineoplastic action against AML cells. Gene silencing due to chromatin compaction is attributable to the action...
Frontiers in genetics, 2012
Gene-environment interactions have long been recognized as a fundamental concept in evolutionary,... more Gene-environment interactions have long been recognized as a fundamental concept in evolutionary, quantitative, and medical genetics. In the genomics era, study of how environment and genome interact to shape gene expression variation is relevant to understanding the genetic architecture of complex phenotypes. While genetic analysis of gene expression variation focused on main effects, little is known about the extent of interaction effects implicating regulatory variants and their consequences on transcriptional variation. Here we survey the current state of the concept of transcriptional gene-environment interactions and discuss its utility for mapping disease phenotypes in light of the insights gained from genome-wide association studies of gene expression.
Proceedings of the National Academy of Sciences, 2012
The host mechanisms responsible for protection against malaria remain poorly understood, with onl... more The host mechanisms responsible for protection against malaria remain poorly understood, with only a few protective genetic effects mapped in humans. Here, we characterize a host-specific genome-wide signature in whole-blood transcriptomes of Plasmodium falciparum -infected West African children and report a demonstration of genotype-by-infection interactions in vivo. Several associations involve transcripts sensitive to infection and implicate complement system, antigen processing and presentation, and T-cell activation (i.e., SLC39A8 , C3AR1 , FCGR3B , RAD21 , RETN , LRRC25 , SLC3A2 , and TAPBP ), including one association that validated a genome-wide association candidate gene ( SCO1 ), implicating binding variation within a noncoding regulatory element. Gene expression profiles in mice infected with Plasmodium chabaudi revealed and validated similar responses and highlighted specific pathways and genes that are likely important responders in both hosts. These results suggest tha...
PLoS Neglected Tropical Diseases, 2013
PLoS Genetics, 2008
The different environments that humans experience are likely to impact physiology and disease sus... more The different environments that humans experience are likely to impact physiology and disease susceptibility. In order to estimate the magnitude of the impact of environment on transcript abundance, we examined gene expression in peripheral blood leukocyte samples from 46 desert nomadic, mountain agrarian and coastal urban Moroccan Amazigh individuals. Despite great expression heterogeneity in humans, as much as one third of the leukocyte transcriptome was found to be associated with differences among regions. Genome-wide polymorphism analysis indicates that genetic differentiation in the total sample is limited and is unlikely to explain the expression divergence. Methylation profiling of 1,505 CpG sites suggests limited contribution of methylation to the observed differences in gene expression. Genetic network analysis further implies that specific aspects of immune function are strongly affected by regional factors and may influence susceptibility to respiratory and inflammatory disease. Our results show a strong genome-wide gene expression signature of regional population differences that presumably include lifestyle, geography, and biotic factors, implying that these can play at least as great a role as genetic divergence in modulating gene expression variation in humans.
PLoS Genetics, 2013
We describe a novel approach to capturing the covariance structure of peripheral blood gene expre... more We describe a novel approach to capturing the covariance structure of peripheral blood gene expression that relies on the identification of highly conserved Axes of variation. Starting with a comparison of microarray transcriptome profiles for a new dataset of 189 healthy adult participants in the Emory-Georgia Tech Center for Health Discovery and Well-Being (CHDWB) cohort, with a previously published study of 208 adult Moroccans, we identify nine Axes each with between 99 and 1,028 strongly co-regulated transcripts in common. Each axis is enriched for gene ontology categories related to subclasses of blood and immune function, including T-cell and B-cell physiology and innate, adaptive, and anti-viral responses. Conservation of the Axes is demonstrated in each of five additional population-based gene expression profiling studies, one of which is robustly associated with Body Mass Index in the CHDWB as well as Finnish and Australian cohorts. Furthermore, ten tightly co-regulated genes can be used to define each Axis as ''Blood Informative Transcripts'' (BITs), generating scores that define an individual with respect to the represented immune activity and blood physiology. We show that environmental factors, including lifestyle differences in Morocco and infection leading to active or latent tuberculosis, significantly impact specific axes, but that there is also significant heritability for the Axis scores. In the context of personalized medicine, reanalysis of the longitudinal profile of one individual during and after infection with two respiratory viruses demonstrates that specific axes also characterize clinical incidents. This mode of analysis suggests the view that, rather than unique subsets of genes marking each class of disease, differential expression reflects movement along the major normal Axes in response to environmental and genetic stimuli.
Nature Genetics, 2009
Studies of the genetics of gene expression can identify expression SNPs (eSNPs) that explain vari... more Studies of the genetics of gene expression can identify expression SNPs (eSNPs) that explain variation in transcript abundance. Here we address the robustness of eSNP associations to environmental geography and population structure in a comparison of 194 Arab and Amazigh individuals from a city and two villages in southern Morocco. Gene expression differed between pairs of locations for up to a third of all transcripts, with notable enrichment of transcripts involved in ribosomal biosynthesis and oxidative phosphorylation. Robust associations were observed in the leukocyte samples: cis eSNPs (P < 10 −08) were identified for 346 genes, and trans eSNPs (P < 10 −11) for 10 genes. All of these associations were consistent both across the three sample locations and after controlling for ancestry and relatedness. No evidence of large-effect transacting mediators of the pervasive environmental influence was found; instead, genetic and environmental factors acted in a largely additive manner.
Leukemia Research, 2012
DNA methylation and histone methylation are both involved in epigenetic regulation of gene expres... more DNA methylation and histone methylation are both involved in epigenetic regulation of gene expression and their dysregulation can play an important role in leukemogenesis. Aberrant DNA methylation has been reported to silence the expression of tumor suppressor genes in leukemia. Overexpression of the histone methyltransferase, EZH2, a subunit of the polycomb group repressive complex 2 (PRC2), was observed to promote oncogenesis. This is due to aberrant gene silencing by the trimethylation of histone H3 lysine 27 (H3K27me3) by EZH2. Since both these epigenetic silencing events are reversible, they are interesting targets for chemotherapeutic intervention by using an inhibitor of DNA methylation, such as 5-aza-2-deoxcytidine (5-AZA-CdR), and 3-deazaneplanocin-A (DZNep), an inhibitor of the EZH2. Human HL-60 and murine L1210 leukemic cells exposed in vitro to 5-AZA-CdR and DZNep in combination showed a synergistic loss of clonogenicity in a colony assay as compared to each agent alone. This positive chemotherapeutic interaction was also observed in mice with L1210 leukemia. Quantitative PCR showed that the combination also produced a remarkable synergistic activation of the tumor suppressor genes, CDKN1A and FBXO32. Microarray analysis showed that 5-AZA-CdR plus DZNep produced a synergistic activation of >150 genes. Our results indicate that 5-AZA-CdR plus DZNep can reactivate target genes that are silenced by two distinct epigenetic mechanisms leading to a loss of the proliferative potential of leukemic cells.
Journal of Medical Genetics, 2013
International Journal of Epidemiology, 2012
The CARTaGENE (CaG) study is both a population-based biobank and the largest ongoing prospective ... more The CARTaGENE (CaG) study is both a population-based biobank and the largest ongoing prospective health study of men and women in Quebec. In population-based cohorts, participants are not recruited for a particular disease but represent a random selection among the population, minimizing the need to correct for bias in measured phenotypes. CaG targeted the segment of the population that is most at risk of developing chronic disorders, that is 40-69 years of age, from four metropolitan areas in Quebec. Over 20 000 participants consented to visiting 1 of 12 assessment sites where detailed health and socio-demographic information, physiological measures and biological samples (blood, serum and urine) were captured for a total of 650 variables. Significant correlations of diseases and chronic conditions are observed across these regions, implicating complex interactions, some of which we describe for major chronic conditions. The CaG study is one of the few population-based cohorts in the world where blood is stored not only for DNA and protein based science but also for gene expression analyses, opening the door for multiple systems genomics approaches that identify genetic and environmental factors associated with disease-related quantitative traits. Interested researchers are encouraged to submit project proposals on the study website (www.cartagene.qc.ca). Why was the cohort set up? Much of what is known about the causes of chronic disorders comes from large epidemiological studies, especially prospective cohorts or population studies from the USA and Europe. 1-4 Because of the significant investment for initial recruitment, specimen collection and storage, cohorts of large sizes did not exist in Canada until recently. CARTaGENE (CaG) is the largest ongoing prospective health study of men and women in Quebec, Canada.
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Papers by Youssef Idaghdour