The aryl hydrocarbon receptor regulates the expression of TIPARP and its cis long non-coding RNA, TIPARP-AS1

Biochem Biophys Res Commun. 2018 Jan 15;495(3):2356-2362. doi: 10.1016/j.bbrc.2017.12.113. Epub 2017 Dec 21.


The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and member of the basic helix-loop-helix-PAS family. AHR is activated by numerous dietary and endogenous compounds that contribute to its regulation of genes in diverse signaling pathways including xenobiotic metabolism, vascular development, immune responses and cell cycle control. However, it is most widely studied for its role in mediating 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity. The AHR target gene and mono-ADP-ribosyltransferase, TCDD-inducible poly-ADP-ribose polymerase (TIPARP), was recently shown to be part of a novel negative feedback loop regulating AHR activity through mono-ADP-ribosylation. However, the molecular characterization of how AHR regulates TIPARP remains elusive. Here we show that activated AHR is recruited to the TIPARP promoter, through its binding to two genomic regions that each contain multiple AHR response elements (AHREs), AHR regulates the expression of both TIPARP but also TIPARP-AS1, a long non-coding RNA (lncRNA) which lies upstream of TIPARP exon 1 and is expressed in the opposite orientation. Reporter gene and deletion studies showed that the distal AHRE cluster predominantly regulated TIPARP expression while the proximal cluster regulated TIPARP-AS1. Moreover, time course and promoter activity assays suggest that TIPARP and TIPARP-AS1 work in concert to regulate AHR signaling. Collectively, these data show an added level of complexity in the AHR signaling cascade which involves lncRNAs, whose functions remain poorly understood.

Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin; Aryl hydrocarbon receptor; Long non-coding RNA; TCDD-Inducible poly-ADP-ribose polymerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • MCF-7 Cells
  • Neoplasms, Experimental / genetics*
  • Neoplasms, Experimental / metabolism*
  • Neoplasms, Experimental / pathology
  • Poly(ADP-ribose) Polymerases / genetics*
  • Poly(ADP-ribose) Polymerases / metabolism*
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism*
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Signal Transduction / genetics


  • RNA, Long Noncoding
  • Receptors, Aryl Hydrocarbon
  • 2,3,7,8-tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase, human
  • Poly(ADP-ribose) Polymerases