Abstract
Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which mediates the effects of a variety of environmental stimuli in multiple tissues. Recent advances in AHR biology have underlined its importance in cells with high developmental potency, including pluripotent stem cells. Nonetheless, there is little data on AHR expression and its role during the initial stages of stem cell differentiation. The purpose of this study was to investigate the temporal pattern of AHR expression during directed differentiation of human embryonic stem cells (hESC) into neural progenitor, early mesoderm and definitive endoderm cells. Additionally, we investigated the effect of the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the gene expression profile in hESCs and differentiated cells by RNA-seq, accompanied by identification of AHR binding sites by ChIP-seq and epigenetic landscape analysis by ATAC-seq. We showed that AHR is differentially regulated in distinct lineages. We provided evidence that TCDD alters gene expression patterns in hESCs and during early differentiation. Additionally, we identified novel potential AHR target genes, which expand our understanding on the role of this protein in different cell types.
Highlights
Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor belonging to the bHLH/PAS family of proteins
We investigated the effect of the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the gene expression profile in human embryonic stem cells (hESC) and differentiated cells by RNA-seq, accompanied by identification of AHR binding sites by ChIP-seq and epigenetic landscape analysis by ATAC-seq
We found 28 upregulated genes, which had TCDD-induced AHR binding within +/−200kbp of TSS (Table 1), suggesting that AHR may be involved in direct transcriptional activation of these genes
Summary
Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor belonging to the bHLH/PAS family of proteins. Upon activation by an agonist, AHR translocates to the nucleus where it is released from its cytoplasmic chaperones and dimerises with its nuclear partner ARNT (AHR nuclear translocator) [1,2]. This heterodimeric complex recognises and binds response elements in regulatory regions of its target genes, recruits cofactors and thereby modulates gene expression. Later studies have established that AHR can be activated by various endogenous and natural ligands, ascribing it an important role in cellular homeostasis, including regulation of the cell cycle, apoptosis, etc. Recent advances in the field have emphasised the role of AHR in cells with high developmental potential i.e., stem cells
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