title: Non-coding RNA derived from the region adjacent to the human HO-1 E2 enhancer selectively regulates HO-1 gene induction by modulating Pol II binding.
abstract: Recent studies have disclosed the function of enhancer RNAs (eRNAs), which are long non-coding RNAs transcribed from gene enhancer regions, in transcriptional regulation. However, it remains unclear whether eRNAs are involved in the regulation of human heme oxygenase-1 gene (HO-1) induction. Here, we report that multiple nuclear-enriched eRNAs are transcribed from the regions adjacent to two human HO-1 enhancers (i.e. the distal E2 and proximal E1 enhancers), and some of these eRNAs are induced by the oxidative stress-causing reagent diethyl maleate (DEM). We demonstrated that the expression of one forward direction (5' to 3') eRNA transcribed from the human HO-1 E2 enhancer region (named human HO-1enhancer RNA E2-3; hereafter called eRNA E2-3) was induced by DEM in an NRF2-dependent manner in HeLa cells. Conversely, knockdown of BACH1, a repressor of HO-1 transcription, further increased DEM-inducible eRNA E2-3 transcription as well as HO-1 expression. In addition, we showed that knockdown of eRNA E2-3 selectively down-regulated DEM-induced HO-1 expression. Furthermore, eRNA E2-3 knockdown attenuated DEM-induced Pol II binding to the promoter and E2 enhancer regions of HO-1 without affecting NRF2 recruitment to the E2 enhancer. These findings indicate that eRNAE2-3 is functional and is required for HO-1 induction.
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maruyama
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Junsei
authors.initials: J
authors.lastname: Mimura
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan itohk@cc.hirosaki-u.ac.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics; D004742:Enhancer Elements, Genetic; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism; D006367:HeLa Cells; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008298:Maleates / Q000494:pharmacology; D008969:Molecular Sequence Data; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism*; D022661:RNA, Untranslated / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D008298:Maleates; D051267:NF-E2-Related Factor 2; D022661:RNA, Untranslated; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D012319:RNA Polymerase II; C014476:diethyl maleate