title: DNA methylation of alternative promoters directs tissue specific expression of Epac2 isoforms.
abstract: Epac 1 and Epac 2 (Epac1/2; exchange factors directly activated by cAMP) are multidomain proteins that mediate cellular responses upon activation by the signaling molecule cAMP. Epac1 is ubiquitously expressed, whereas Epac2 exhibits a restricted expression pattern. The gene encoding Epac2 gives rise to at least three protein isoforms (Epac2A, Epac2B and Epac2C) that exhibit confined tissue and cell specific expression profiles. Here, we describe alternative promoter usage for the different isoforms of Epac2, and demonstrate that the activity of these promoters depend on the DNA methylation status. Bisulfite sequencing demonstrated that the level of methylation of the promoters in different tissues correlates with Epac2 isoform expression. The presented data indicate that the tissue-specific expression of the Epac2 isoforms is epigenetically regulated, and identify tissue-specific differentially methylated promoter regions within the Epac2 locus that are essential for its transcriptional control.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Erling A
authors.initials: EA
authors.lastname: Hoivik
authors.forename: Solveig L
authors.initials: SL
authors.lastname: Witsoe
authors.forename: Inger R
authors.initials: IR
authors.lastname: Bergheim
authors.forename: Yunjian
authors.initials: Y
authors.lastname: Xu
authors.forename: Ida
authors.initials: I
authors.lastname: Jakobsson
authors.forename: Anders
authors.initials: A
authors.lastname: Tengholm
authors.forename: Stein Ove
authors.initials: SO
authors.lastname: Doskeland
authors.forename: Marit
authors.initials: M
authors.lastname: Bakke
mesh_terms: D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D017930:Genes, Reporter; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D020033:Protein Isoforms; C486707:Rapgef4 protein, mouse; D008156:Luciferases