Environmental toxicants can induce changes in the epigenomic status of exposed cells, resulting in altered gene expression, which can consequently lead to human diseases such as cancer. The Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is expected to play a key role in this process upon exposure to these toxicants. However, how these epigenomic changes are brought about in response to environmental toxicant exposure is far from being understood. One major toxicant is the prototypical polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P) which is found in air pollution generated by incomplete combustion of organic materials. To understand important upstream events for implementing epigenomic status in response to environmental toxicants, we will study the effect of B[a]P on higher-order chromatin structure (such as chromatin looping formed via inter- or intra-chromosomal interactions). Epigenomic status and subsequent gene expression profiles of individual genes are governed at the level of higher-order chromatin structure. We will address the role of the genome organizer protein SATB1 in the process of conformational changes of chromatin induced by B[a]P. SATB1 can establish higher-order chromatin folding, affect the epigenomic status at hundreds of its target genes, and reprogram gene expression genome-wide in response to external signaling. Thus, we propose the hypothesis that SATB1 is a critical driver in executing the effects of environmental toxicants in affected cells at the level of higher-order chromatin structure. If so, the gene regulatory role of the ligand-activated AhR after B[a]P exposure would be greatly altered under the influence of SATB1. We will determine the effect of gene expression patterns in response to B[a]P exposure using our breast epithelial MCF10A tumor progression series, containing SATB1- expressing and non-expressing cells. We will determine genomic binding sites of AhR (and its associating partner, ARNT) and SATB1 by chromatin immunoprecipitation, followed by deep sequencing to find if any SATB1 and AhR-ARNT complex binding sites merge upon B[a]P exposure, and we will examine the biological consequences of B[a]P exposure of the cells expressing varying levels of SATB1.
We aim to assess whether B[a]P exposure promotes malignancy to a degree dependent on the SATB1 levels in the exposed cells. The potential role of a genome organizer in controlling ligand-activated AhR after exposure to environmental toxicants has never been addressed to date, and testing this hypothesis will likely provide a valuable new perspective for the field of environmental health science.
Increasing evidence suggests that the epigenomic modification of chromatin changes when cells are exposed to environmental toxicants. How these changes are brought about remains to be investigated. We will test a novel hypothesis that the genome organizer SATB1 regulates higher-order chromatin structure in breast epithelial cells upon exposure to an environmental toxicant, benzo[a]pyrene, thereby changes the epigenomic modification and expression of genes.
