Here are some of the projects we are working on.

Reconstructed AHR transcriptional regulatory network in the liver.

Reconstructed AHR transcriptional regulatory network in the liver.

Inference of ahr signaling netwoRk in the liver

The aryl hydrocarbon receptor (AHR), a ligand-inducible transcription factor (TF) activated by the persistent environmental contaminant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and other dioxin-like chemicals, is an enigmatic molecule with a controversial endogenous role. Ligand-activated TFs like the AHR underlie most of the major cellular stress response pathways. The inactivated TF is typically sequestered in the cytoplasm or nucleus. Upon activation by its ligand (endogenous or exogenous molecule), the TF is able to bind specific response elements in the promoter regions of target genes and activate or inhibit coordinated expression of suites of genes. However, only a small subset of target genes in TF-governed pathways are regulated in this “classical” manner. We are working to unravel the structure and dynamics of the molecular networks underlying activation of the AHR pathway. Using gene expression and genome-wide AHR binding data sets, we have found that the classical model of direct target gene regulation accounts for only about 10% of gene perturbations in TCDD-exposed mouse liver. The AHR pathway does not act in isolation but is instead embedded in a hierarchical network comprised of multiple gene regulatory interactions. Genes in this network bound by similar groups of TFs show similar expression patterns, thus establishing a link between gene co-regulation and co-expression. Furthermore, co-regulated gene clusters activate distinct groups of downstream biological processes, with the AHR-bound genes enriched for metabolic processes and AHR-unbound genes primarily activating immune processes. This ongoing work illustrates the application of bioinformatic and statistical tools for reconstruction and analysis of the transcriptional regulatory cascades underlying adverse cellular response.



Denali National Park

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This One Tree Somewhere

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By Tyne & Wear Archives & Museums [No restrictions], via Wikimedia Commons