Effects of Non-Cellular Factors on Gene Expression
Effects of mitochrondria on nuclear gene expression
Mitochondrial dysfunction is one of the most notable features of cancer cells. Mitochondria of rapidly growing tumor cells are fewer in number and smaller in size and exhibit a variety of altered morphologies when compared to those in normal cells. Somatic mutations in mitochondrial DNA are found in 30% to 100% of all tumors studied. The role of the altered mitochondrial genome in tumor growth is unclear. Recent studies with transmitochondrial cybrids revealed that the presence of cancer cell–derived mitochondria could alter the behavior of the host cell. In order to understand the genetic basis of this phenomenon, we examined host cell gene profile in transmitochondrial cybrids with mitochondria derived from breast cancer cells. Preliminary results indicated distinct differences in nuclear gene expression between cybrids with normal mitochondria and cybrids with cancer cell–derived mitochrondria.. We also observed marked differences in nuclear gene expression patterns between cybrids harboring different cancer cell–derived mitochrondria that behave differently with respect to tumorigenicity and various key regulators in energy metabolism. Importantly, the gene signatures of these cybrids mimic the breast cancer profile. To reveal the potential transcriptional regulators of this gene set, promoter analysis was performed. Of the 12 known genes validated by real-time PCR, 5 genes (42%) demonstrated the presence of TP53 binding site, while NF-kappaB binding sites were present in 6 genes (50%). Four genes contain sites for both factors. The potential regulation by p53 or NF-KappaB was also confirmed through reconstruction of gene networks by systems biological analysis. These results suggested that mitochondria derived from breast cancer cell lines could communicate and effect transcription activities of the nucleus. Thus, genetically altered mitochondria may actively participate in breast cancer development. This is a collaborative study with Dr. Lee-Jun Wong of the Department of Human Genetics, Baylor College of Medicine.
Genomic effects of naked ceria nanoparticles
Despite the myriad applications of nanoparticles and possible high human exposure, the impact of manufactured nanoparticles on the environment and human health is not clear. Most studies on the biological effects of nanoparticles focused on the activities of functional components, such as drugs, proteins, antibodies, etc., conjugated to the nanoparticles. More recently, some naked nanoparticles were found to be cytotoxic and affect cellular activities. Envirox, a trade name for naked cerium oxide (CeO2) nanoparticle used as a diesel fuel additive, has been demonstrated to reduce fuel consumption and the emission of carbon dioxide and particulate from vehicles. However the health impact of CeO2 nanoparticles is poorly understood. To generate a detailed, unbiased assessment of the molecular responses to CeO2 nanoparticles (CeO-6, 6 nm), we conducted a genomic study to identify gene expression signatures associated with nanoparticle exposure in a murine neuronal cell (HT22) model. We controlled for the effect of particle size using 1000 nm diameter cerium oxide (CeO-M) and for the effect of chemical property using 300 nm diameter aluminum oxide particles (AlO). We demonstrated cerium oxide nanoparticles induced chemical- and size-specific changes in the transcriptome of murine neuronal cells. The genes whose expression is affected by the presence of CeO-6 are related to neurological disease, cell cycle control and growth. On the other hand, similar studies with human mesenchymal stem cells revealed the induction of osteogenic factors by CeO-6. These observations indicate that nanoparticles are capable of inducing size- and chemistry-specific changes in cells and caution the use and need for in-depth assessment of potential health risks of nanoparticle exposure. This is a collaborative study with Dr. Siu-Wai Chan of Columbia University.