title: Role of CTCF in Regulating SLC45A3-ELK4 Chimeric RNA.
abstract: The chimeric RNA, SLC45A3-ELK4, was found to be a product of cis-splicing between the two adjacent genes (cis-SAGe). Despite the biological and clinical significance of SLC45A3-ELK4, its generating mechanism has not been elucidated. It was shown in one cell line that the binding of transcription factor CTCF to the insulators located at or near the gene boundaries, inversely correlates with the level of the chimera. To investigate the mechanism of such cis-SAGe events, we sequenced potential regions that may play a role in such transcriptional read-through. We could not detect mutations at the transcription termination site, insulator sites, splicing sites, or within CTCF itself in LNCaP cells, thus suggesting a "soft-wired" mechanism in regulating the cis-SAGe event. To investigate the role CTCF plays in regulating the chimeric RNA expression, we compared the levels of CTCF binding to the insulators in different cell lines, as well as clinical samples. Surprisingly, we did not find an inverse correlation between CTCF level, or its bindings to the insulators and SLC45A3-ELK4 expression among different samples. However, in three prostate cancer cell lines, different environmental factors can cause the expression levels of the chimeric RNA to change, and these changes do inversely correlate with CTCF level, and/or its bindings to the insulators. We thus conclude that CTCF and its bindings to the insulators are not the primary reasons for differential SLC45A3-ELK4 expression in different cell lines, or clinical cases. However, they are the likely mechanism for the same cells to respond to different environmental cues, in order to regulate the expression of SLC45A3-ELK4 chimeric RNA. This response to different environmental cues is not general to other cis-SAGe events, as we only found one out of 16 newly identified chimeric RNAs showing a pattern similar to SLC45A3-ELK4.
authors.affiliation: Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Fujun
authors.initials: F
authors.lastname: Qin
authors.affiliation: Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Yansu
authors.initials: Y
authors.lastname: Song
authors.affiliation: Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Loryn
authors.initials: L
authors.lastname: Facemire
authors.affiliation: Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Henry
authors.initials: H
authors.lastname: Frierson
authors.affiliation: Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.|Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins; D009154:Mutation; D017354:Point Mutation; D011471:Prostatic Neoplasms / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D050808:ets-Domain Protein Elk-4 / Q000378:metabolism*
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C494193:ELK4 protein, human; D026901:Membrane Transport Proteins; D009004:Monosaccharide Transport Proteins; D012097:Repressor Proteins; C551031:SLC45a3 protein, human; D050808:ets-Domain Protein Elk-4; D012313:RNA