You are here:
A Cellular Game of Telephone: Trans Tissue Reprogramming of Responses to Toxic Stimuli
Citation:
Vitucci, E., G. Budziszewski, AND S. McCullough. A Cellular Game of Telephone: Trans Tissue Reprogramming of Responses to Toxic Stimuli. Gordon Research Conference in Cellular and Molecular Mechanisms of Toxicity, Andover, NH, August 12 - 18, 2017.
Impact/Purpose:
Increases understanding of how inhaled exposures cause systemic health effects. Dr. McCullough added Cooperative Agreement Number CR82952201
Description:
Exposure to air pollution is a leading cause of cardiopulmonary morbidity and mortality; however, while these effects outside the lung have been associated with aberrant oxidative stress and inflammation, the underlying molecular mechanisms are poorly understood. We hypothesized that air pollutant exposure of human bronchial epithelial cells (HBEC) could alter the expression of pro-inflammatory and oxidative stress genes in adjacent, but physically separated cells through alterations to the epigenome. To test this hypothesis confluent monolayers of HBEC grown on permeable membranes were exposed to diesel exhaust particles (DEP) while monocytic THP-1 cells were present in the basolateral compartment. A variety of both pro-inflammatory (e.g. IL-8, IL1-alpha, IL1-beta) and oxidative stress genes (NQO1, GCLM, GCLC, and HMOX1) were induced in THP-1 cells cultured in the presence of DEP-exposed HBEC. Using IL-8 and HMOX1 as representative genes in the pro-inflammatory and oxidative stress responses, respectively, we then determined whether these changes in gene expression were associated with alterations to the epigenome. We assessed the abundance of four histone modifications with established roles as key regulators of gene expression – trimethyl histone H3 lysine 4 (H3K4me3), pan-acetyl H4 (H4ac), di/trimethyl histone H3K27 (H3K27me2/3), and unmodified H3 as a marker of chromatin density. The abundance of H3K4me3 and H3K27me2/3 increased within the promoters of both IL-8 and HMOX1 in THP-1 cells cultured in the presence of DEP-exposed HBEC. Similarly, these indirectly exposed THP-1 cells also exhibited hyperacetylation of H4 within IL-8 and HMOX1 enhancer regions. These changes in histone modifications were accompanied by a local reduction in H3 occupancy in these regions, suggesting a more open chromatin conformation. This non cell-autonomous epigenetic reprogramming within the THP-1 cells was also associated with an enhanced pro-inflammatory and oxidative stress response to a secondary challenge with lipopolysaccharide (LPS). Our findings demonstrate that pollutant-exposed epithelial cells reprogram the expression and responsiveness of pro-inflammatory and oxidative stress genes in adjacent cells at the epigenetic level in a non-cell autonomous manner. This discovery further heightens the importance of understanding the relationship between environmental factors such as air pollutants and human health and provides a potential mechanism by which exposure to air pollution can cause adverse health effects in tissues that are not directly exposed.