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

Nucleic Acids Res. 2014 Dec 16;42(22):13599-614. doi: 10.1093/nar/gku1169. Epub 2014 Nov 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / genetics
  • Enhancer Elements, Genetic*
  • Fanconi Anemia Complementation Group Proteins / metabolism
  • HeLa Cells
  • Heme Oxygenase-1 / biosynthesis
  • Heme Oxygenase-1 / genetics*
  • Humans
  • Maleates / pharmacology
  • Molecular Sequence Data
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress
  • Promoter Regions, Genetic
  • RNA Polymerase II / metabolism*
  • RNA, Untranslated / biosynthesis
  • RNA, Untranslated / genetics
  • RNA, Untranslated / metabolism*
  • Transcriptional Activation*


  • BACH1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • Fanconi Anemia Complementation Group Proteins
  • Maleates
  • NF-E2-Related Factor 2
  • RNA, Untranslated
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • RNA Polymerase II
  • diethyl maleate

Associated data

  • GENBANK/AB905426
  • GENBANK/AB905427
  • GENBANK/AB905428
  • GENBANK/AB905429