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

Abstract

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.

Loss of Tiparp Results in Aberrant Layering of the Cerebral Cortex

“…Moreover, the absence of Ahr expression compromises GABAergic neuron cell differentiation in the ventral telencephalon (Huang et al, 2004; Gohlke et al, 2009). Tiparp expression is induced by Ahr, which in turn regulates Ahr signaling as part of a negative feedback loop (MacPherson et al, 2013; Grimaldi et al, 2018). Therefore, loss of Tiparp could result in hyperactivation of Ahr signaling, which could partly explain our findings.…”

Knockdown of LINC01116 inhibits cell migration and invasion in head and neck squamous cell carcinoma through epithelial‐mesenchymal transition pathway

“…7 They are often aberrantly expressed in various squamous cell carcinomas, such as esophageal cancer, 8 prostate cancer, 9 bladder cancer, 10 and head and neck squamous cell carcinoma, 11 and function as oncogenes or tumor suppressors. 7 They are often aberrantly expressed in various squamous cell carcinomas, such as esophageal cancer, 8 prostate cancer, 9 bladder cancer, 10 and head and neck squamous cell carcinoma, 11 and function as oncogenes or tumor suppressors.…”

From cirrhosis to hepatocellular carcinomaAn investigation into hepatitis C viral oncogenesis

“…[35] We also noted cell signaling pathways linked to oncogenesis, such as up-regulation of genes involved in G protein-coupled signaling RGS1, RGS2, and in the pro-oncogenic pathway aryl hydrocarbon signaling, such as TIPARP. [36][37][38][39] We found the up-regulation of the frizzled gene receptor FZD7, which causes increased Wnt/Beta-catenin activity and is associated with HCC. [40] Soluble FZD7 inhibits Wnt signaling and sensitizes HCC cell lines towards doxorubicin.…”