Genome-wide DNA methylation reprogramming in response to inorganic arsenic links inhibition of CTCF binding, DNMT expression and cellular transformation.
Chronic low dose inorganic arsenic (iAs) exposure leads to changes in gene expression and epithelial-to-mesenchymal transformation. During this transformation, cells adopt a fibroblast-like phenotype accompanied by profound gene expression changes. While many mechanisms have been implicated in this transformation, studies that focus on the role of epigenetic alterations in this process are just emerging. DNA methylation controls gene expression in physiologic and pathologic states. Several studies show alterations in DNA methylation patterns in iAs-mediated pathogenesis, but these studies focused on single genes. We present a comprehensive genome-wide DNA methylation analysis using methyl-sequencing to measure changes between normal and iAs-transformed cells. Additionally, these differential methylation changes correlated positively with changes in gene expression and alternative splicing. Interestingly, most of these differentially methylated genes function in cell adhesion and communication pathways. To gain insight into how genomic DNA methylation patterns are regulated during iAs-mediated carcinogenesis, we show that iAs probably targets CTCF binding at the promoter of DNA methyltransferases, regulating their expression. These findings reveal how CTCF binding regulates DNA methyltransferase to reprogram the methylome in response to an environmental toxin.
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
Matthew
M
Rea
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
Meredith
M
Eckstein
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
Rebekah
R
Eleazer
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.|Bellarmine University, Louisville, KY 40205, USA.
Caroline
C
Smith
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
Yvonne N
YN
Fondufe-Mittendorf
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D001151:Arsenic / Q000633:toxicity*; D000076246:CCCTC-Binding Factor / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000473:pathology; D065150:Cellular Reprogramming / Q000187:drug effects / Q000235:genetics*; D002877:Chromosomes, Human; D018899:CpG Islands / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D063990:Gene Ontology; D015894:Genome, Human; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D015203:Reproducibility of Results; D014158:Transcription, Genetic / Q000187:drug effects
D000076246:CCCTC-Binding Factor; D004248:DNA (Cytosine-5-)-Methyltransferases; D001151:Arsenic