title: Inorganic Arsenic-induced cellular transformation is coupled with genome wide changes in chromatin structure, transcriptome and splicing patterns.
abstract: BACKGROUND
  Arsenic (As) exposure is a significant worldwide environmental health concern. Low dose, chronic arsenic exposure has been associated with a higher than normal risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. While arsenic-induced biological changes play a role in disease pathology, little is known about the dynamic cellular changes resulting from arsenic exposure and withdrawal.
  
  
  RESULTS
  In these studies, we sought to understand the molecular mechanisms behind the biological changes induced by arsenic exposure. A comprehensive global approach was employed to determine genome-wide changes to chromatin structure, transcriptome patterns and splicing patterns in response to chronic low dose arsenic and its subsequent withdrawal. Our results show that cells exposed to chronic low doses of sodium arsenite have distinct temporal and coordinated chromatin, gene expression, and miRNA changes consistent with differentiation and activation of multiple biochemical pathways. Most of these temporal patterns in gene expression are reversed when arsenic is withdrawn. However, some gene expression patterns remained altered, plausibly as a result of an adaptive response by cells. Additionally, the correlation of changes to gene expression and chromatin structure solidify the role of chromatin structure in gene regulatory changes due to arsenite exposure. Lastly, we show that arsenite exposure influences gene regulation both at the initiation of transcription as well as at the level of splicing.
  
  
  CONCLUSIONS
  Our results show that adaptation of cells to iAs-mediated EMT is coupled to changes in chromatin structure effecting differential transcriptional and splicing patterns of genes. These studies provide new insights into the mechanism of iAs-mediated pathology, which includes epigenetic chromatin changes coupled with changes to the transcriptome and splicing patterns of key genes.
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA. caitlyn.riedmann@uky.edu.
authors: Caitlyn
authors: C
authors: Riedmann
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA. ye.ma@stu.fayette.kyschools.us.
authors: Ye
authors: Y
authors: Ma
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA. Manana.Melikishvili@uky.edu.
authors: Manana
authors: M
authors: Melikishvili
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA. sggodfrey@trevecca.edu.
authors: Steven Grason
authors: SG
authors: Godfrey
authors: Graduate Center for Toxicology, University of Kentucky, Lexington, KY, 40536, USA. Zhuo.zhnag@uky.edu.
authors: Zhou
authors: Z
authors: Zhang
authors: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, 40536, USA. kueyc@uky.edu.
authors: Kuey Chu
authors: KC
authors: Chen
authors: Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY, 40292, USA. eric.rouchka@louisville.edu.
authors: Eric C
authors: EC
authors: Rouchka
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA. y.fondufe-mittendorf@uky.edu.
authors: Yvonne N
authors: YN
authors: Fondufe-Mittendorf
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000633:toxicity*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000633:toxicity*; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D018053:Arsenites; D002843:Chromatin; D035683:MicroRNAs; D009707:Nucleosomes; D017670:Sodium Compounds; C017947:sodium arsenite