The G&E Program is broadly focused on the fundamental genetic, epigenetic, and genomic mechanisms that control cell growth and differentiation, and that cause cancer and other human diseases. From basic science investigations to translational studies, G&E students and faculty are actively engaged in the pursuit of new scientific knowledge that could one day lead to clinical advances. Below are the broad areas of research being performed in G&E Program labs.
- Developmental Genetics
- Human Genetics
- Cancer Genetics
- Genome Maintenance & Repair
Nearly every cell in our body has the exact same genome, yet that DNA blueprint is interpreted differently in specific settings to create many different cell types. How is the same genetic code read so differently to generate this cellular diversity? How do defects in reading the code lead to pathologies?
The answers to these questions are found in the study of epigenetics, which refers to heritable phenotypic changes that are not mediated by changes in DNA sequence but rather by alterations in genome organization.
DNA is highly compacted within the eukaryotic nucleus in the form of chromatin, which is built from repeating units of histone-DNA particles called nucleosomes. Nucleosome placement, density, and higher order folding all impact accessibility of DNA sequences to transcription factors and regulatory proteins, thereby affecting patterns of gene expression.
Changes in chromatin structure control where, when and at what level genes are expressed during embryogenesis and after birth. They also control cellular responses to environmental and physiological changes. Moreover, proper chromatin organization is crucial for maintenance of genome integrity.
Epigenetic abnormalities are associated with loss of cell identity, genome instability, deregulated growth, and abnormal response to signal transduction pathways, thereby contributing to disease states.
The G&E Program faculty are defining how epigenetic factors impact gene transcription, DNA recombination, DNA repair, and DNA replication in normal cells in order to understand how epigenetic abnormalities contribute to cancer development and progression.
Since epigenetic changes are often reversible, our studies provide strong molecular frameworks for the development of new therapies targeting regulators of key epigenetic events such as DNA methylation, histone modifications, or expression of non-coding RNAs.
It is remarkable that a single cell, the fertilized egg, will consistently form an individual with differentiated tissues and organs, positioned correctly within the body. What are the genes that regulate these processes during embryogenesis? How do different cells and tissues interact to form functional organs and organ systems? Which genes when mutated lead to birth defects?
These types of questions can be answered by studying developmental genetics, which focuses on genes and genetic pathways that regulate embryological, postnatal, and regenerative processes.
In the G&E Program, numerous labs utilize genetic approaches in model organisms including Drosophila, C. elegans, Xenopus, zebrafish, and mouse, to study a variety of developmental processes.
These processes include cell fate and differentiation, inductive interactions between tissues, tissue morphogenesis and organogenesis, and stem cell biology and regeneration. A primary strength using these model systems is that these studies are predominantly carried out in vivo.
Interestingly, many of the genes used by the embryo during development are also deployed later in the adult organism to regulate physiological processes, including homeostasis, wound healing and regeneration. Thus, many of the G&E Program labs exploit these model systems to study genes involved in physiological processes that when altered lead to pathologies that mimic human diseases. Basic knowledge produced by developmental studies fuels translational and clinical research that one day will lead to disease therapies.
Why do some people have an increased lifetime risk for developing cancer or chronic conditions such as cardiovascular and neurodegenerative disease? Is there a genetic explanation for the repeated occurrence of these conditions among members of the same family? What are the genetic variants inherited within families that can be detected and linked to these conditions?
The answers to these questions are found in the study of human genetics. Human genetics research has the primary goal of identifying the molecular basis of inherited disorders, elucidating the genetic and genomic basis of chronic conditions, as well as developing computational tools based on analytical methods to identify disease susceptibility loci and individuals at risk for developing disease.
Human genetics research involves utilizing a broad set of techniques and knowledge, including the basic principles of molecular biology, mendelian genetics and the latest genomic tools, including next-generation DNA sequencing and bioinformatics.
G&E Program faculty are identifying mutations and genetic variants that provide a molecular explanation of inherited human diseases. Understanding the molecular basis of human genetic diseases can lead to disease prevention and the development of treatments and cures.
Cancer is a genetic disease. Mutations that cause cancer alter fundamental cell behaviors, including growth, proliferation, and migration. How do you identify genes that influence cancer formation and progression?
One way is to use human genetics to identify cancer-causing gene mutations that are inherited. Another way is to correlate genetic lesions found in sporadically occurring tumors. A powerful approach to identify and understand cancer-causing genes is to use model organisms.
In the G&E Program, these model organisms include the fruit fly (Drosophila), the nematode worm (C. elegans), zebrafish, and the mouse. These systems can be used for large-scale in vivo genetic screens to identify cancer-causing genes or candidate cancer-causing genes can be engineered to create models of human cancer. These powerful genetic systems have led to the identification of genetic pathways that regulate cell behaviors that when mutated lead to tumor formation and metastasis.
Human patients and families with genetic defects contribute to our studies and help inform our thinking as we ultimately hope that this knowledge can provide cures.
Genome Maintenance and Repair
The genome is constantly being challenged by internal and external forces that cause DNA damage. DNA damage results from both programmed cellular processes, such as those required for meiotic crossover and antibody diversity, and spontaneous damage, such as errors in DNA replication, the cellular generation of damage-inducing chemicals, exposure to irradiation or chemicals present in the environment.
Cells have developed many distinct ways to repair DNA damage, but not all DNA damage is properly repaired. Incorrectly repaired DNA damage can lead to genome rearrangements from point mutations to chromosome breaks or loss. Incorrectly repaired DNA can also lead to programmed cell death.
How do cells recognize, respond to and correctly repair DNA damage? How does improper repair influence genome stability? How does failure to repair lead to programmed cell death? How do cancer cells with genome damage bypass cell death?
Many G&E Program laboratories are uncovering how cells recognize and respond to DNA damage, with an emphasis on the genetic and epigenetic factors involved in these processes. G&E Program labs are defining the protein complexes and enzymatic activities that recognize and repair different types of DNA damage, while discovering signaling pathways induced to impose cell cycle checkpoints, to facilitate DNA repair, and to promote other cellular process such as programmed cell death. Ultimately these discoveries will lead to novel strategies for increasing the vulnerability of cancer cells to specific therapeutic strategies.