Epigenetics

Cell metabolism is a tightly controlled process that uses numerous feedback and feed-forward mechanisms to provide the necessary requirements to sustain growth. Many of these regulatory mechanisms are mediated through the post-translational modification of enzymes that serve to modulate activity and function. My laboratory studies the link between cell metabolism, protein post-translational modifications, and gene expression. We utilize mass spectrometry to investigate both novel and established metabolic feedback mechanisms and how these go awry in disease. Current work centers on histone modifications derived from cell metabolism and how these modifications are disrupted in diabetes and cancer.

My major interests include epigenetic regulation of angiogenesis and vascular development. Angiogenesis plays a critical role in both physiological and pathological conditions. I am investigating various mechanisms involved in angiogenesis with development and aging of organisms and its role in organ development as well as cancers.

My other area of investigation is involving adipose-derived stem cells and their usefulness in treating osteoarthritis, diabetes, stroke, traumatic brain injury, myocardial infarction, and spinal cord injuries following road traffic accidents.

Alex Badyaev’s research focus is at the interface of evolutionary developmental biology and evolutionary ecology, with specific focus on the understanding of the origin of adaptations. The central goal of his work is to understand the evolution of organismal architecture that reconciles innovation and adaptation. Under this general umbrella, Badyaev lab studies the following empirical themes: 1) Origin, development, and evolution of avian color diversity, 2) Epigenetic remodeling and genetic adaptation in ontogeny of skeletal structures, 3) Relationship between epigenetic and genetic inheritance systems, 4) Role of stress in origin and diversification of organismal forms, 5) Evolution of behavioral and life history strategies, and 6) Evolution and ecology of sexual size dimorphism.

Catharine Smith, PhD, focuses on epigenetic mechanisms of gene expression, particularly their regulation through signaling pathways and their modulation by anti-cancer drugs. Epigenetic mechanisms play a very important role in transcriptional regulation of genes but the specifics of these mechanisms require ongoing study. A very exciting new area of research focuses on how these mechanisms are disrupted during tumorigenesis but may also be harnessed to treat cancer. Signaling pathways control the expression of key genes in non-cancerous cells but are often misregulated during the process of oncogenesis. Chromatin proteins and transcription factors that interact with chromatin are often targets of these pathways. Two projects in the lab are directed at the interface of signaling pathways and chromatin. First, Dr. Smith is interested in the mechanism by which the female reproductive steroid, progesterone, regulates target genes in the physiological context of chromatin. Chronic progestin exposure has been linked to increased incidence of breast cancer in post-menopausal women on hormone-replacement therapy. However, the function of the progesterone receptor in mammary tissue and its role in oncogenesis are not well understood. Current studies in this area are directed at the role of chaperone proteins in determining how the progesterone receptor functions at target genes in chromatin and how it is impacted by other signaling pathways.Second, her lab has discovered a novel cAMP signaling pathway that regulates cell cycle progression and are focused on identifying specific components and targets of this pathway.Third, histone deacetylases (HDACs) are key transcriptional regulatory proteins. Inhibitors that target these enzymes have shown great promise as anti-cancer drugs and are currently in clinical trials. However, a lack of knowledge of HDAC biology has made it difficult to predict which tumors will respond to these drugs. HDACs are known to participate in gene repression, but recent work indicates that they are also transcriptional coactivators. Further studies on the mechanism of gene repression through HDAC inhibitors will provide insight into the role of these enzymes as coactivators.

Rebecca Mosher, PhD, studies how epigenetic information is passed from parent to offspring. Epigenetic information refers to signals laid on top of DNA sequence that affect how and when genes are turned on. Examples of epigenetic signals include chemical modifications of DNA, packaging of DNA around proteins, or the position of DNA in the nucleus. Beginning with Mendel’s observations of pea plants, we have developed a robust understanding of how genetic information in the form of DNA is passed from parent to offspring, but we are only beginning to comprehend how and when epigenetic information is passed from generation to generation. Some epigenetic marks are erased and re-established during reproduction, while others are inherited for many generations. Using plants as models, the Mosher lab studies how tiny RNA molecules place and erase epigenetic marks during reproduction and how the epigenetic marks from the maternal and paternal genomes interact after fertilization.

Sean W. Limesand, PhD, is an Associate Professor in the School of Animal and Comparative Biomedical Sciences at the University of Arizona in the College of Agriculture and Life Sciences. He is also a member of the UA’s BIO5 Institute and Department of Obstetrics and Gynecology. Dr. Limesand is nationally and internationally recognized for his work studying fetal endocrinology and metabolism in pregnancy and in pregnancies compromised by pathology such as intrauterine growth restriction and diabetes. His research is focused on defining developmental consequences resulting from a compromised intrauterine environment. Specifically, he is focused on fetal adaptations in insulin secretion and action that when altered in utero create lifelong metabolic complications. Dr. Limesand has lead the charge on prenatal origins of –cell dysfunction as the Principal Investigator for a number of federal and foundation grant awards and published more than 40 peer-reviewed articles on topics related to this research. Keywords: Diabetes, Pregnancy, Perinatal Biology

Bernard Futscher, PhD, and his lab focus on the molecular origins of human cancer. More specifically, the lab group has 3 inter-related research objectives based on the underlying concept that developing an in-depth understanding of epigenetic mechanismsresponsible for governing cell fate will allow for the development of more effective strategies for the prevention, treatment, and cure of cancer. First, they wish to identify which epigenetic mechanisms participate in the transcriptional control of genes important to growth and differentiation. Second, they seek to determine how these epigenetic mechanisms, and therefore epigenetic homeostasis, become compromised during oncogenesis. Third, using a new and more complete understanding of epigenetic control of the genome, Dr. Futscher and his team are developing rational new therapeutic strategies that seek to repair these defects in the cancer cell and transcriptionally reprogram the malignant cancer cell to a benign state. To reach their objectives, a variety of in vitro models of cancer have been developed to address emerging hypotheses that are inferred from the literature in basic and clinical science as well as our own data. Results from these in vitro studies are then translated to the clinical situation to determine their meaning in the actual clinical face of the disease. Similarly, they attempt to take information obtained from the genome-wide assessment of clinical specimens in order to help guide our thinking and develop new hypotheses that can be tested experimentally in our in vitro models.