Tony Gill
Genetics Graduate Student in the Whitehead Lab
University of California - Davis
University of California - Davis
Tiny specialized vibration detectors called hair cells send signals from the inner ear to the brain that are interpreted as sound and spatial orientation. If too many of these microscopic structures are destroyed by disease or injury, permanent hearing loss can occur. That may be a problem for humans and other mammals, but not for fish, amphibians, reptiles, and birds. They can regenerate their hair cells and avoid going deaf.
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The human apolipoprotein E (APOE) gene plays an important role in lipid metabolism. It has three common genetic variants, alleles ɛ2/ɛ3/ɛ4, which translate into three protein isoforms of apoE2, E3 and E4. These isoforms can differentially influence total serum cholesterol levels; therefore, APOE has been linked with cardiovascular disease. Additionally, its ɛ4 allele is strongly associated with the risk of Alzheimer's disease (AD), whereas the ɛ2 allele appears to have a modest protective effect for AD. Despite decades of research having illuminated multiple functional differences among the three apoE isoforms, the precise mechanisms through which different APOE alleles modify diseases risk remain incompletely understood. In this study, we examined the genomic structure of APOE in search for properties that may contribute novel biological consequences to the risk of disease. We identify one such element in the ɛ2/ɛ3/ɛ4 allele-carrying 3′-exon of APOE. We show that this exon is imbedded in a well-defined CpG island (CGI) that is highly methylated in the human postmortem brain. We demonstrate that this APOE CGI exhibits transcriptional enhancer/silencer activity. We provide evidence that this APOE CGI differentially modulates expression of genes at the APOE locus in a cell type-, DNA methylation- and ɛ2/ɛ3/ɛ4 allele-specific manner. These findings implicate a novel functional role for a 3′-exon CGI and support a modified mechanism of action for APOE in disease risk, involving not only the protein isoforms but also an epigenetically regulated transcriptional program at the APOE locus driven by the APOE CGI.
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Crude oils from distinct geological sources worldwide are toxic to developing fish hearts. When oil spills occur in fish spawning habitats, natural resource injury assessments often rely on conventional morphometric analyses of heart form and function. The extent to which visible indicators correspond to molecular markers for cardiovascular stress is unknown for pelagic predators from the Gulf of Mexico. Here we exposed mahi (Coryphaena hippurus) embryos to field-collected crude oil samples from the 2010 Deepwater Horizon disaster. We compared visible heart defects (edema, abnormal looping, reduced contractility) to changes in expression of cardiac-specific genes that are diagnostic of heart failure in humans or associated with loss-of-function zebrafish cardiac mutants. Mahi exposed to crude oil during embryogenesis displayed typical symptoms of cardiogenic syndrome as larvae. Contractility, looping and circulatory defects were evident, but larval mahi did not exhibit downstream craniofacial and body axis abnormalities. A gradation of oil exposures yielded concentration-responsive changes in morphometric and molecular responses, with relative sensitivity being influenced by age. Our findings suggest that 1) morphometric analyses of cardiac function are more sensitive to proximal effects of crude oil-derived chemicals on the developing heart and 2) molecular indicators reveal a longer-term adverse shift in cardiogenesis trajectory. See more here The potential bioavailability of toxic chemicals from oil spills to water column organisms such as fish embryos may be influenced by physical dispersion along an energy gradient. For example, a surface slick with minimal wave action (low energy) could potentially produce different toxic effects from high energy situations such as pressurized discharge from a blown wellhead. Here we directly compared the toxicity of water accommodated fractions (WAFs) of oil prepared with low and high mixing energy (LEWAFs and HEWAFs, respectively) using surface oil samples collected during the 2010 Deepwater Horizon spill, and embryos of a representative nearshore species, red drum (Sciaenops ocellatus). Biological effects of each WAF type was quantified with several functional and morphological indices of developmental cardiotoxicity, providing additional insight into species-specific responses to oil exposure. Although the two WAF preparations yielded different profiles of polycyclic aromatic hydrocarbons (PAHs), cardiotoxic phenotypes were essentially identical. Based on benchmark thresholds for both morphological and functional cardiotoxicity, in general LEWAFs had lower thresholds for these phenotypes than HEWAFs based on total PAH measures. However, HEWAF and LEWAF toxicity thresholds were more similar when calculated based on estimates of dissolved PAHs only. Differences in thresholds were attributable to the weathering state of the oil samples.
See more here Metabolic disease is a leading cause of death worldwide, and obesity, a central risk factor, is reaching epidemic proportions. Energy expenditure and brown adipose tissue (BAT) thermogenesis are implicated in metabolic disease, and it is becoming evident that impaired BAT activity is regulated by gene/environment interactions. Peroxisome proliferator-activated receptor γ coactivator 1α (Pgc-1α) is a critical regulator of BAT thermogenesis, which is highly inducible by environmental stimuli such as cold and diet. Some of my research focuses on the environmentally mediated epigenetic and transcriptional regulation of Pgc-1α gene expression during BAT thermogenesis. Specifically, interactions between histone modifications and transcription factors at the Pgc-1α promoter that cause BAT Pgc-1α transcription in response to cold. Histone modifications also modulate BAT Pgc-1α transcription in response to nutrients though diet has been less characterized than cold with respect to regulation of Pgc-1α transcription. We find that Pgc-1α DNA methylation and RNA expression is also correlated to indicators of adiposity and glucose homeostasis across numerous human tissues. Although post-translational modification of Pgc-1α protein has been well-characterized across diverse tissues and environments, comparatively little is known of the epigenetic mechanisms regulating Pgc-1α transcription, particularly in BAT thermogenesis.
See more here The Exxon Valdez oil spill occurred March 24, 1989, when herring were preparing to spawn in Prince William Sound. The herring population experienced an unanticipated, abrupt decline three years later, due - in part - to a mortality from infectious and parasitic diseases. Linking the oil spill to subsequent population collapse remains controversial. A major insight from years of studying the spill is that embryonic herring are profoundly sensitive to crude oil; exposure to vanishingly low levels of oil over a brief time early in a herring’s life-cycle can have long-lasting health effects, and oil exposure can disturb immune function. Could crude oil exposure during early life have compromised immune system development, thereby increasing the risk of major disease outbreak in later life? To address this question, over the past few years we have sought to simulate the events surrounding the 1993 herring collapse using 1) experimental exposures to environmentally relevant levels of Alaska north slope crude oil, 2) fish from the Prince William Sound population and others, and 3) the same pathogens that caused the disease outbreak. Embryonic and larval herring were exposed to low levels of oil, left to recover and grow-up in clean seawater, then exposed to pathogens. Through this research, we are examining links between the Exxon Valdez oil spill from 1989 to the 1993 collapse of the fishery. shared with permission by NOAA/NWFSC
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AuthorHello - I am Tony Gill and I study how chemicals affect development ArchivesCategories |