Converging Roles of the Aryl Hydrocarbon Receptor in Early Embryonic Development, Maintenance of Stemness, and Tissue Repair

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor well-known for its adaptive role as a sensor of environmental toxicants and mediator of the metabolic detoxification of xenobiotic ligands. In addition, a growing body of experimental data has provided indisputable evidence that the AHR regulates critical functions of cell physiology and embryonic development. Recent studies have shown that the naïve AHR-that is, unliganded to xenobiotics but activated endogenously-has a crucial role in maintenance of embryonic stem cell pluripotency, tissue repair, and regulation of cancer stem cell stemness. Depending on the cellular context, AHR silences the expression of pluripotency genes Oct4 and Nanog and potentiates differentiation, whereas curtailing cellular plasticity and stemness. In these processes, AHR-mediated contextual responses and outcomes are dictated by changes of interacting partners in signaling pathways, gene networks, and cell-type-specific genomic structures. In this review, we focus on AHR-mediated changes of genomic architecture as an emerging mechanism for the AHR to regulate gene expression at the transcriptional level. Collective evidence places this receptor as a physiological hub connecting multiple biological processes whose disruption impacts on embryonic development, tissue repair, and maintenance or loss of stemness.

Keywords: Ah receptor; embryonic development; stemness; tissue repair.

Figure 1.

Crosstalk between the AHR and pluripotency factor in pluripotent state and during differentiation. A, In pluripotent ES cells, complexes of OCT4, NANOG, and SOX2 cooperate with Polycomb Group Repressive Complexes PRC1/2 to bind to a distal silencer domain in the Ahr upstream region and actively repress AHR expression. Unproductive RNA polymerase II is paused at the Ahr transcription start site and drives the synthesis of short abortive transcripts. B, During differentiation, AHR expression is derepressed by reversal of repressive marks in the Ahr promoter chromatin, release of pluripotency factors and PcG proteins, binding of Sp factors, establishment of histone marks of open chromatin, and engagement of active RNAPII to drive full-length RNA transcript elongation. C, In human embryonal carcinoma cells, AHR suppresses OCT4 and NANOG expression by binding to flanking Alu elements. This generates short noncoding RNA transcripts that target the degradation of OCT4 and NANOG mRNA through the RISC complex. At the NANOG locus, AHR cooperatively binds with CTCF, thus initiating chromatin looping and heterochromatinization around the NANOG gene leading to silencing of NANOG expression to allow differentiation to proceed.

Figure 2.

Ahr regulates tissue repair and regeneration. The activated AHR is known to induce the expression of the G1-phase cyclin-dependent kinase inhibitor p27^Kip1 thus delaying the cell cycle. In addition, the pluripotency factors OCT4, SOX2, and NANOG are upregulated in the absence of AHR. These changes likely bring about stasis in cell proliferation and depletion of the stem cell pool. Thus, tissue repair proceeds swiftly in the absence of AHR, and lags upon AHR activation.

Figure 3.

Cooccupancy of AHR-binding sites by complexes of AHR and CTCF. A, Statistics summarizing locations of AHR binding sites in TCDD-treated MCF7 cells. Public sequencing data was downloaded from Geo Omnibus where it is available with the accession number GSE90550 (Yang et al. 2018). B, AHR, CTCF, and RAD21 binding profile across 47 dioxin-responsive genes in TCDD-treated MCF7 cells (Tomblin et al. 2016). Strongest AHR binding was observed in gene bodies, which were cooccupied by CTCF and RAD21. SRA database files SRR5057971, SRR10096218, and SRR10096220 were downloaded from http://ncbi.github.io/sra-tools/ and used to generate bam files. DeepTools was used to generate the 1× RPGC-normalized bigwig files from the bam files and to calculate signal values. C, AHR, CTCF, and RAD21 binding across candidate enhancer locations in MCF7 cells. AHR cooperatively binds the enhancers with CTCF and RAD21. MCF7 STARR-seq databases obtained from ENCODE (ENCFF356ZLC) and were analyzed the same way as in Figure 2B. TSS: transcription start site, TTS: transcription termination site, TES: transcription end site.