Aryl hydrocarbon receptor-induced activation of the human IGH hs1.2 enhancer: Mutational analysis of putative regulatory binding motifs
| Autor: | Andrew David Snyder, Sharon D. Ochs, Courtney E. W. Sulentic, Brooke E. Johnson |
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| Rok vydání: | 2020 |
| Předmět: |
Transcriptional Activation
0301 basic medicine Polychlorinated Dibenzodioxins Genes Immunoglobulin Heavy Chain Immunology medicine.disease_cause Article Cell Line Mice 03 medical and health sciences 0302 clinical medicine Tandem repeat Basic Helix-Loop-Helix Transcription Factors medicine Animals Humans Binding site Enhancer Molecular Biology Transcription factor Regulation of gene expression Mutation Binding Sites Base Sequence biology Chemistry Aryl hydrocarbon receptor Cell biology DNA binding site Enhancer Elements Genetic 030104 developmental biology Receptors Aryl Hydrocarbon Mutagenesis Site-Directed biology.protein 030215 immunology |
| Zdroj: | Mol Immunol |
| ISSN: | 0161-5890 |
| Popis: | The human hs1.2 enhancer within the Ig heavy chain gene (IGH) is polymorphic and associated with a number of autoimmune diseases. The polymorphic region is characterized by tandem repeats of an ∼53-bp invariant sequence containing possible binding sites for several transcription factors. Our previous studies suggest the human hs1.2 enhancer is sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental toxicant and high affinity ligand of the aryl hydrocarbon receptor (AhR). TCDD induced hs1.2 enhancer activity in an AhR-dependent manner and the number of invariant sequences influenced the magnitude of activity. To better understand the regulation of human hs1.2 enhancer activity, the objective of the current study was to utilize mutational analysis and luciferase reporter constructs to evaluate the contribution of putative transcription factor binding sites to overall hs1.2 enhancer activity and modulation by TCDD. Basal and LPS-induced activity of the hs1.2 enhancer appeared to be most affected by mutation of sites outside of the invariant sequence or deletion of the entire invariant sequence; whereas sites influencing the effect of TCDD were dependent on the cellular activation state (i.e. unstimulated vs. LPS stimulation) and relatively independent of the putative AhR binding site within the invariant sequence. These results suggest that AhR activation affects human hs1.2 activity through an as yet undetermined non-canonical pathway. A better understanding regarding the role of the hs1.2 enhancer in human Ig expression and how AhR ligands modulate its activity may lead to insights into overall Ig regulation and mechanisms of dysfunction. |
| Databáze: | OpenAIRE |
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