Bioinformatics Centre > Local news > New article in Toxicol...

2010-04-13

New article in Toxicological Sciences

Eivind Valen and collegues have published an article in Toxicological Sciences on the AhR receptor and its binding sites. This has beena  collaboration with Jason Metthews group at the university ofToronto. The article is available here , and the abstract is below:

The aryl hydrocarbon receptor (AHR) is a ligand-activated protein that mediates the toxic actions of polycyclic aromatic and halogenated compounds. Identifying genes directly regulated by AHR is important in understanding the pathways regulated by this receptor. Here we used chromatin immunoprecipitation and promoter focused microarrays (ChIP-chip) to detect AHR bound genomic regions after 3-methylcholanthrene (3MC) treatment of T-47D human breast cancer cells. We identified 241 AHR-3MC bound regions and transcription factor binding site analysis revealed a strong over-representation of the AHR responsive element. Conventional ChIP confirmed recruitment of AHR to 26 regions with target gene responses to 3MC varying from activation to inhibition to having no effect. A comparison of identified AHR-3MC bound regions with AHR-TCDD bound regions in from our previous study (Ahmed, S., Valen, E., Sandelin, A. & Matthews, J 2009 Toxicol Sci, 111, 254-266), revealed that 127 regions were common between the data sets. Time course ChIPs for six of the regions showed that 3MC-induced gene-specific changes in histone H3 acetylation and methylation, and induced differential oscillatory binding of AHR, with a periodicity between 1.5 to 2 h. Re-treatment of cells with 3MC failed to alter the oscillatory binding profiles of AHR or ARNT. Cells became responsive to 3MC but not TCDD after 24 h of exposure to 3MC, highlighting important differences in AHR responsiveness between the two ligands. Our results reveal a number of novel AHR-bound promoter regions and target genes that exhibit differential kinetic binding profiles and regulation by AHR.