title: Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells.
abstract: Stem cells, especially human embryonic stem cells (hESCs), are useful models to study molecular mechanisms of human disorders that originate during gestation. Alcohol (ethanol, EtOH) consumption during pregnancy causes a variety of prenatal and postnatal disorders collectively referred to as fetal alcohol spectrum disorders (FASDs). To better understand the molecular events leading to FASDs, we performed a genome-wide analysis of EtOH's effects on the maintenance and differentiation of hESCs in culture. Gene Co-expression Network Analysis showed significant alterations in gene profiles of EtOH-treated differentiated or undifferentiated hESCs, particularly those associated with molecular pathways for metabolic processes, oxidative stress, and neuronal properties of stem cells. A genome-wide DNA methylome analysis revealed widespread EtOH-induced alterations with significant hypermethylation of many regions of chromosomes. Undifferentiated hESCs were more vulnerable to EtOH's effect than their differentiated counterparts, with methylation on the promoter regions of chromosomes 2, 16 and 18 in undifferentiated hESCs most affected by EtOH exposure. Combined transcriptomic and DNA methylomic analysis produced a list of differentiation-related genes dysregulated by EtOH-induced DNA methylation changes, which likely play a role in EtOH-induced decreases in hESC pluripotency. DNA sequence motif analysis of genes epigenetically altered by EtOH identified major motifs representing potential binding sites for transcription factors. These findings should help in deciphering the precise mechanisms of alcohol-induced teratogenesis.
authors.affiliation: Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA 90095, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Khalid
authors.affiliation: Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA 90095, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA 90095, USA.
authors.forename: Hyun-Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA 90095, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoang
authors.affiliation: Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA 90095, USA.
authors.forename: Thanh G
authors.initials: TG
authors.lastname: Tu
authors.affiliation: Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA 90095, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Elie
authors.affiliation: Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA 90095, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Lee
authors.affiliation: Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA 90095, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vu
authors.affiliation: Department of Human Genetics and Biostatistics, UCLA David Geffen School of Medicine, Box 957088, 4357A Gonda Center, Los Angeles, CA 90095, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.affiliation: Division of Oral Biology & Medicine, UCLA School of Dentistry, 10833 Le Conte Avenue, 63-078 CHS, Los Angeles, CA 90095, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Spigelman
authors.affiliation: Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA 90095, USA.|Division of Oral Biology & Medicine, UCLA School of Dentistry, 10833 Le Conte Avenue, 73-022 CHS, Los Angeles, CA 90095, USA.|UCLA's Jonsson Comprehensive Cancer Center, 8-684 Factor Building, Box 951781, Los Angeles, CA 90095, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Kim
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000431:Ethanol / Q000009:adverse effects*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans
chemical_list: D000431:Ethanol
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