Cell & Molecular Biology Graduate Group

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Kelsey Johnson, Voight lab (matriculated 2013)

Macintosh HD:Users:sundaram:Desktop:Documents:GGR stuff:Website updates 2014:Student highlights pages:Kelsey Johnson.jpg


I joined the Voight Lab in June 2014 and began working on a project studying signals of positive selection in the human genome. Using data from the 1000 Genomes Project, I am identifying regions showing evidence of selective sweeps in 14 populations and quantifying the degree of sharing of sweeps between those populations. Sweeps may be shared between populations due to common ancestry, migration and gene flow, convergent evolution, or by chance. I plan to use shared sweeps to investigate the evolutionary history of these populations and potentially identify the selected adaptive variants in these regions.

   

Sumeet Khetarpal, Rader Lab (matriculated 2010)

SumeetI started my thesis work in the Rader Lab in 2012 with the goal of understanding how human genetics can identify causal mechanisms and therapeutic targets linking blood lipid traits to heart disease. For one of my projects, I studied the GALNT2 gene, a novel locus associated with lipid traits identified from genome-wide association studies that encodes an enzyme involved in O-glycosylation of proteins. Through studies in humans, rodents, and nonhuman primate models of GALNT2 deficiency, I demonstratedthat GALNT2 is likely the causal gene at this locus associated with lipids and that it regulates high-density lipoprotein (HDL) metabolism through the glycosylation function of the encoded enzyme in a cross-species manner. In another project, I identified arare loss-of-function variant in the SCARB1 gene which encodes a receptor for HDL cholesterol. I found that this variant confers very high levels of HDL cholesterol in the blood but increased risk of heart disease in humans, which contrasts with longstanding epidemiology suggesting that high HDL cholesterol is protective from disease. This work suggests that mechanisms regulating metabolismand clearanceof HDL cholesterol may ultimately be more important than HDL cholesterol levels themselves in influencing risk of heart disease. A third major project I focused on was the study of a rare coding variant in the APOC3 gene, which encodes a protein ApoC-III that delays the turnover of triglycerides in the blood. High triglycerides are associated with increased risk of heart disease and rare coding variants in APOC3 have been associated with reduced triglycerides and protection from disease. Through studying the mechanism of action of one of these protective variants, I have found a clearance pathway for ApoC-III that may aid in therapeutic targeting of this protein.

   

Joyce Lee, Wellen Lab (matriculated 2011)

Joyce LeeI started working with Dr. Kathryn Wellen in 2012. I am her first graduate student trainee, and my research is on understanding the interactions between metabolism and epigenetics. To balance biosynthesis and growth, cells need to sense and respond to nutrient levels in the cell—an emerging mechanism to accomplish this is nutrient-sensitive protein acetylation. Glucose regulates global histone acetylation in multiple cell lines in a dose-dependent manner, resulting in concomitant changes in gene expression. Mechanistically, glucose-dependent histone acetylation is regulated through an acetyl-CoA producing enzyme, ATP-citrate lyase (ACLY). My goals are to fill the gaps in understanding how acetyl-CoA regulated histone acetylation directs functional consequences in cancer cells via gene regulation. This work will contribute to our understanding of how changes in cellular metabolism can promote cancer phenotypes.

 

Suzanne Shapira, Seale Lab (matriculated 2012)

ShapiraMy work in the Seale lab focuses on understanding the molecular mechanisms by which a specialized type of adipose tissue called brown fat develops and functions. There is currently an urgent demand for new strategies to treat and prevent obesity and its associated diseases. A promising approach to combat these metabolic disorders is through enhancing the endogenous cellular mechanisms that can increase energy expenditure. Thermogenic brown adipose tissue is specialized to burn energy through lipid catabolism to produce heat. In mice and humans, increasing the activity of these fat cells leads to increased energy expenditure and decreased body fat mass. The transcription factor Early B-Cell Factor 2 (EBF2) is an essential mediator of brown adipocyte commitment and terminal differentiation. However, the mechanisms by which EBF2 regulates chromatin to activate brown fat-specific genes in adipocytes are currently unknown. We have employed modern genomic, genetic, and epigenetic tools to address this question. ChIP-seq analyses show that EBF2 binds to brown fat lineage-specific enhancers and that loss of EBF2 decreases markers of enhancer activity at these regions. Mechanistically, EBF2 physically interacts with the chromatin remodeler BRG1 and the BAF chromatin remodeling complex in brown adipocytes. This complex, which acquires tissue-specific functions through combinatorial assembly of non-catalytic subunits, dynamically alters chromatin structure to facilitate access of transcriptional machinery to regulatory elements in the genome. Notably, we have identified DPF3 as a brown fat-selective component of the BAF-complex, which is required for brown fat gene programming. Loss of DPF3in brown adipocytes reduces chromatin accessibility at EBF2-bound enhancers and leads to a significant decrease in basal and catecholamine-stimulated expression of brown fat-selective genes. Furthermore,Dpf3is a direct transcriptional target of EBF2 during brown adipocyte differentiation, thereby establishing a regulatory loop through which EBF2 activates and also recruits DPF3-anchored BAF complexes to chromatin. Together, these results reveal a novel mechanism by which EBF2 cooperates with tissue-specific remodeling complexes to activate brown fat-identity genes, thus enhancing our knowledge of how this energy-burning tissue functions.

 

Ellie Weisz, Jongens lab (matriculated 2011)

Macintosh HD:Users:sundaram:Desktop:Documents:GGR stuff:Website updates 2014:Student highlights pages:Ellie Weisz.JPGMy work in the Jongens laboratory has been focused on studying metabolism in a Drosophila model of Fragile X Syndrome (FXS). This project is particularly relevant on a translational level given that FXS is the most common heritable form of intellectual impairment and the leading genetic cause of autism. In addition to behavioral, cognitive, and physical abnormalities, the clinical literature suggests that individuals with FXS show signs of metabolic dysfunction. Despite these observations, no studies have been conducted to assess metabolism in human patients or animal models of the disease.One genetic model that has emerged as a powerful tool to study Fragile X disease pathology is Drosophila melanogaster, as flies homozygous for amorphic alleles of the Drosophila ortholog of the pathological gene in humans display behavioral, cognitive, and neuroanatomical phenotypes that are remarkably similar to those found in human patients. Recently, research from our laboratory has suggested that insulin signaling is dysregulated in the Drosophila model of FXS. Since proper regulation of insulin signaling is critical to maintain metabolic homeostasis, it is my hypothesis that metabolism is altered in the fly model of FXS. Moreover, I believe that these metabolic differences may affect behavioral and cognitive output.

Thus far I have identified striking metabolic phenotypes in Fragile X flies. Specifically, my data suggest that glycogen and triglyceride levels are drastically reduced in our model. Consequently, the Fragile X flies are much less resistant to starvation than their wild-type counterparts. These findings are particularly interesting given that my data also indicate that the Fragile X flies consume more food than wild-type flies. A similar hyperphagia phenotype has been observed in human patients, however, my studies are the first to demonstrate this in an animal model of the disease. Now that I have identified robust metabolic phenotypes in our model, my goal is to identify the molecular and genetic mechanisms underlying these changes. Further, I plan to utilize the wide array of genetic tools in Drosophila to identify the cells that are relevant to the observed metabolic changes. Finally, I plan to determine whether genetic and/or pharmacological manipulation of proteins involved in metabolism can rescue the observed behavioral, cognitive, and neuroanatomical abnormalities in our Fragile X model.