A novel system for understanding the effects of natural genetic variation and epigenetics of stem cells.
Understanding stem cell regulation holds the potential to treat many diseases. However, some experiments that would aid this understanding cannot be performed with humans due to ethics or practicality. One concern is whether the DNA marks (i.e. epigenetics) regulating stem cells and other genes are stable in cells grown in culture over long term. This is particularly important in that it is clear that cancers are also caused by stem cells. The effects of genetic variation on stem cells are also little known.
Studies of house mouse stem cells have partly filled this gap. There are significant differences between house mouse stem and human stem cells. It is not clear whether these are simply species differences, or may partly reflect the artificial genetic make-up of laboratory mouse strains. For example, it is becoming clear that the complete inbreeding of the lab strains has affected their genome, and that the combination of genetic variants seen in these animals does not exist in nature. Further, these animals have been domesticated and selected for traits that do not exist in the wild (analogous to differences between poodles and wolves).
Our system is unique in using animals with natural genetic variation. We use the most common Native American mammals, rodents of the genus Peromyscus. While these animals are commonly called deer or field mice, they are only distantly related to house mice and rats. One of many differences is that these animals live over twice as long as house mice. Captive strains derived from actual populations are available. Severe prenatal defects occur in hybrids between several of these populations are known. Many of these defects resemble human diseases. A common outcome is a growth with placental like tissues but no fetus. This is similar to a disease relatively common in California termed molar pregnancy.
We have evidence that abnormal regulation of stem cells is involved in the hybrid defects. The research proposed here proposes to use these animals to study: 1. the stem cell basis of the hybrid defects, 2. the natural genetic variants that affect stem cells, 3. the stability of stem cell epigenetic marks of over long periods of time.
Understanding of stem cell regulation has the potential to treat or prevent many diseases. These diseases are not limited to those requiring regenerative capacity, but include cancers and developmental defects. Human studies on some aspects of stem cell biology are unethical or impractical. Current animal models are highly genetically modified relative to their ancestors. Our proposal suggests a new system that may be used to understand the role of natural genetic variation on stem cell regulation, and the stability of cultured stem cells. The proposed system also utilizes native California wildlife. We therefore expect several types of benefit to the Citizens of California. First, our studies will likely suggest genetic variants and epigenetic profiles that will lead to improved human studies or therapies. Second, these animals may provide an alternative system for use bybiotech and pharmaceutical companies. Third, the research will provide graduate and undergraduate student research opportunities, and brings together several disparate areas of biological study. Finally, better understanding of native species, and the role of environment on epigenetics may ultimately benefit our care of the ecosystem.