Computational selection and prioritization of candidate genes for Fetal Alcohol Syndrome

Lombard, Zané; Tiffin, Nicki; Hofmann, Oliver; Bajic, Vladimir B.; Hide, Winston; Ramsay, Michèle

doi:10.1186/1471-2164-8-389

Cited by 36 publications

(30 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In rats, a microarray study of 28,000 genes was conducted; 304 placental genes were altered by greater than twofold by alcohol (46). Utilizing a computational gene expression mining approach, a study illustrated candidate pathways including TGF-␤ and MAPK signaling (32). Another study using mathematical modeling of microarray gene expression data from alcohol-treated mouse embryos identified candidate transcription factor and microRNA binding sites (56).…”

Section: Discussionmentioning

confidence: 99%

Multiplexed digital quantification of binge-like alcohol-mediated alterations in maternal uterine angiogenic mRNA transcriptome

Ramadoss

Magness

2012

Physiological Genomics

View full text Add to dashboard Cite

Genomic studies on fetal alcohol spectrum disorders (FASD) have utilized either genome-wide microarrays/bioinformatics or targeted real-time PCR (RT-PCR). We utilized herein for the first time a novel digital approach with high throughput as well as the capability to focus on one physiological system. The aim of the present study was to investigate alcohol-induced alterations in uterine angiogenesis-related mRNA abundance using digital mRNA technology. Four biological and three technical replicates of uterine arterial endothelial cells from third-trimester ewes were fluorescence-activated cell sorted, validated, and treated without or with binge-like alcohol. A capture probe covalently bound to an oligonucleotide containing biotin and a color-coded reporter probe were designed for 85 angiogenesis-related genes and analyzed with the Nanostring nCounter system. Twenty genes were downregulated (↓) and two upregulated (↑), including angiogenic growth factors/receptors (↓placental growth factor), adhesion molecules (↓angiopoietin-like-3; ↓collagen-18A1; ↓endoglin), proteases/matrix proteins/inhibitors (↓alanyl aminopeptidase; ↓collagen-4A3; ↓heparanase; ↓plasminogen, ↑plasminogen activator urokinase; ↓platelet factor-4; ↓plexin domain containing-1; ↓tissue inhibitor of metalloproteinases-3), transcription/signaling molecules (↓heart and neural crest derivatives-2; ↓DNA-binding protein inhibitor; ↓NOTCH-4; ↓ribosomal protein-L13a1; ↓ribosomal protein large-P1), cytokines/chemokines (↓interleukin-1B), and miscellaneous growth factors (↓leptin; ↓platelet-derived growth factor-α); ↓transforming growth factor (TGF-α; ↑TGF-β receptor-1). These novel data show significant detrimental alcohol effects on genes controlling angiogenesis supporting a mechanistic role for abnormal uteroplacental vascular development in FASD. The tripartite digital gene expression system is therefore a valuable tool to answer many additional questions about FASD from both mechanistic as well as ameliorative perspectives.

show abstract

Section: Discussionmentioning

confidence: 99%

Multiplexed digital quantification of binge-like alcohol-mediated alterations in maternal uterine angiogenic mRNA transcriptome

Ramadoss

Magness

2012

Physiological Genomics

View full text Add to dashboard Cite

show abstract

“…The use of computational selection and candidate gene prioritization identified MAPK among leading candidate genes for susceptibility to FAS (3). Therefore, we studied ERK1/2 modulation of ethanol sensitivity in two model systems in which ethanol always inhibits L1 adhesion: 2A2-L1 s , an NIH/3T3 clonal cell line that stably expresses hL1, and NG108-15, a neural cell line that expresses mL1 after treatment with bone morphogenetic proteins (17,19,23,38,39).…”

Section: Resultsmentioning

confidence: 99%

“…P renatal alcohol exposure causes fetal alcohol spectrum disorders (FASD) in up to 2-5% of school-age children and is the leading preventable cause of mental retardation in the Western world (1,2). The prevalence and presentation of FASD are influenced by the quantity, frequency, and timing of drinking and are modified by a variety of environmental, nutritional, epigenetic, and genetic factors (3)(4)(5)(6)(7). The observation that there is greater concordance for fetal alcohol syndrome (FAS) in monozygotic twins than in dizygotic twins suggests that there are susceptibility genes for FASD (8); however, their identification remains elusive.…”

mentioning

confidence: 99%

Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule

Dou

Wilkemeyer

Menkari

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

There is a genetic contribution to fetal alcohol spectrum disorders (FASD), but the identification of candidate genes has been elusive. Ethanol may cause FASD in part by decreasing the adhesion of the developmentally critical L1 cell adhesion molecule through interactions with an alcohol binding pocket on the extracellular domain. Pharmacologic inhibition or genetic knockdown of ERK2 did not alter L1 adhesion, but markedly decreased ethanol inhibition of L1 adhesion in NIH/3T3 cells and NG108-15 cells. Likewise, leucine replacement of S1248, an ERK2 substrate on the L1 cytoplasmic domain, did not decrease L1 adhesion, but abolished ethanol inhibition of L1 adhesion. Stable transfection of NIH/3T3 cells with human L1 resulted in clonal cell lines in which L1 adhesion was consistently sensitive or insensitive to ethanol for more than a decade. ERK2 activity and S1248 phosphorylation were greater in ethanol-sensitive NIH/3T3 clonal cell lines than in their ethanol-insensitive counterparts. Ethanol-insensitive cells became ethanol sensitive after increasing ERK2 activity by transfection with a constitutively active MAP kinase kinase 1. Finally, embryos from two substrains of C57BL mice that differ in susceptibility to ethanol teratogenesis showed corresponding differences in MAPK activity. Our data suggest that ERK2 phosphorylation of S1248 modulates ethanol inhibition of L1 adhesion by inside-out signaling and that differential regulation of ERK2 signaling might contribute to genetic susceptibility to FASD. Moreover, identification of a specific locus that regulates ethanol sensitivity, but not L1 function, might facilitate the rational design of drugs that block ethanol neurotoxicity. P renatal alcohol exposure causes fetal alcohol spectrum disorders (FASD) in up to 2-5% of school-age children and is the leading preventable cause of mental retardation in the Western world (1, 2). The prevalence and presentation of FASD are influenced by the quantity, frequency, and timing of drinking and are modified by a variety of environmental, nutritional, epigenetic, and genetic factors (3-7). The observation that there is greater concordance for fetal alcohol syndrome (FAS) in monozygotic twins than in dizygotic twins suggests that there are susceptibility genes for FASD (8); however, their identification remains elusive. The identification of molecular pathways that regulate sensitivity to ethanol teratogenesis would be helpful in the search for FASD susceptibility genes.One potentially important target of ethanol in the pathogenesis of FASD is the developmentally critical immunoglobulin neural cell adhesion molecule, L1. The homophilic binding of L1 molecules on adjacent cells mediates neuronal migration, axon guidance, and axon fasciculation (9)-developmental events that are disrupted in FASD (10-12). Mutations in the human L1 gene cause brain lesions and neurological abnormalities. Some of these mutations also disrupt L1 homophilic binding (13-16). We noted that brain lesions in children with FASD resemble those of child...

show abstract

“…An initial list of 90 to 100 genes mined from published literature 24 will serve as the starting point. SNPs with haplotype tagging potential will also be favored, and we focus on SNPs with reasonable allele frequency (≥30%) in the population.…”

Section: Research Planmentioning

confidence: 99%

Fetal Alcohol Spectrum Disorders: Gene-Environment Interactions, Predictive Biomarkers, and the Relationship Between Structural Alterations in the Brain and Functional Outcomes

Reynolds

Weinberg

Clarren³

et al. 2011

Seminars in Pediatric Neurology

View full text Add to dashboard Cite

Prenatal alcohol exposure is a major, preventable cause of behavioral and cognitive deficits in children. Despite extensive research, a unique neurobehavioral profile for children affected by prenatal alcohol exposure remains elusive. A fundamental question that must be addressed is how genetic and environmental factors interact with gestational alcohol exposure to produce neurobehavioral and neurobiological deficits in children. The core objectives of the NeuroDevNet team in fetal alcohol spectrum disorders is to create an integrated research program of basic and clinical investigations that will (1) identify genetic and epigenetic modifications that may be predictive of the neurobehavioral and neurobiological dysfunctions in offspring induced by gestational alcohol exposure and (2) determine the relationship between structural alterations in the brain induced by gestational alcohol exposure and functional outcomes in offspring. The overarching hypothesis to be tested is that neurobehavioral and neurobiological dysfunctions induced by gestational alcohol exposure are correlated with the genetic background of the affected child and/or epigenetic modifications in gene expression. The identification of genetic and/or epigenetic markers that are predictive of the severity of behavioral and cognitive deficits in children affected by gestational alcohol exposure will have a profound impact on our ability to identify children at risk.

show abstract

Computational selection and prioritization of candidate genes for Fetal Alcohol Syndrome

Cited by 36 publications

References 99 publications

Multiplexed digital quantification of binge-like alcohol-mediated alterations in maternal uterine angiogenic mRNA transcriptome

Multiplexed digital quantification of binge-like alcohol-mediated alterations in maternal uterine angiogenic mRNA transcriptome

Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule

Fetal Alcohol Spectrum Disorders: Gene-Environment Interactions, Predictive Biomarkers, and the Relationship Between Structural Alterations in the Brain and Functional Outcomes

Contact Info

Product

Resources

About