Events

Sep

BMG Seminar: PRINCIPLES OF EPIGENETICS AND CHROMATIN IN DEVELOPMENT AND HUMAN DISEASE - Ali Shilatifard, PhD

Chicago - 10:00 AM - 11:00 AM

Epigenetic regulation of gene expression in metazoans is central for establishing cellular diversity, and the perturbation of this process results in pathological conditions. Although transcription factors are essential for implementing gene expression programs, they do not function in isolation and require the recruitment of various chromatin-modifying and remodeling machineries. A classic example of developmental gene expression through chromatin is the regulation of the balanced activities of the Polycomb group (PcG) proteins within the PRC1 and PRC2 complexes, and the Trithorax group (TrxG) proteins within the COMPASS family. Recent large-scale genome sequencing efforts of human cancer have demonstrated that PcG and COMPASS subunits are highly mutated in a large number of human solid tumors and hematological malignancies. I will discuss our laboratory’s latest biochemical and genetic studies defining the molecular properties of COMPASS and PcG families in the regulation of gene expression, during development, the central role they play in cancer pathogenesis, and how we have taken advantage of such basic molecular information to develop targeted therapeutics for the treatment of hematological malignancies, pediatric brain cancer, and other forms of solid tumors. Ali Shilatifard, PhD Chair, Department of Biochemistry and Molecular GeneticsDirector, Simpson Querrey Center for EpigeneticsRobert Francis Furchgott ProfessorProfessor of Biochemistry and Molecular Genetics and Pediatrics Northwestern University, Feinberg School of Medicine

Sep

BMG Guest Seminar Speaker: Judd F. Hultquist, PhD

Chicago - 10:00 AM - 11:00 AM

The Department of Biochemistry and Molecular Genetics presents: Judd F Hultquist, PhDAssistant Professor of Medicine (Infectious Diseases)Robert H. Lurie Medical Research Center

Sep

BMG Seminar: Decoding the cancer genome one codon at a time and its therapeutic implications -Davide Ruggero, PhD

Chicago - 10:00 AM - 11:00 AM

Our research is centered on understanding translational control of gene expression in both normal health and disease, with a particular focus on cancer biology. Our research combines mouse genetics with genome-wide translational profiling, in-depth molecular biology, and pharmacology to systematically define the points of regulation, in cis and trans, by which the genome is selectively decoded into proteins in a cell- and tissue-specific manner. We have uncovered that a common denominator of multiple oncogenic pathways is their ability to directly control the core translation machinery of a cell, resulting in the rapid remodeling of mRNA translation programs that promote distinct hallmarks of cancer development, such as cell growth, metabolism, and increased motility. Our most recent findings delineate the in vivo requirements for a distinct threshold of the major cap-binding protein, eIF4E, in normal organismal development compared to those required for translating the cancer genome. We show that increased eIF4E activity is essential for cancer cell survival as distinct subsets of mRNAs that regulate the cancer cell oxidative response are marked by the presence of a novel, eIF4E-dependent cis-acting motif present in their 5’UTRs. I will also discuss a new link between translational nutrient availability to maintain metabolic fitness and health span in vivo. In particular, we are defining the role of translation regulation for the first time in the poorly understood molecular program underlying increased risk of cancer development associated with obesity. I will also discuss the generation of the first comprehensive systems-level analysis of the ‘cancer translatome’ during cancer development in vivo that highlights a dichotomy in transcriptional vs. translational control of gene expression guiding key, select steps in cancer development and evolution. The immediate impact of our research has been the design of a new generation of compounds to target the aberrant translation machinery in cancer cells, which are currently in clinical trials, and may reflect a new frontier in cancer therapy. Davide Ruggero, PhDProfessor, Department of UrologyHelen Diller Family Chair in Basic Cancer ResearchUniversity of California San Francisco

Oct

BMG Seminar: Chaperone discovery and characterization -James Bardwell, PhD

Chicago - 10:00 AM - 11:00 AM

Protein folding in the cell relies heavily on chaperones. Even though much has been learned about chaperones, particularly in regard to their co-chaperone and co-factor requirements, observing how chaperones bind to a wide range of substrate proteins and affect their folding has proven to be very difficult. This difficulty primarily comes from two sources: the functional complexity of chaperone machines, and the fact that chaperone substrates are almost always poorly defined mixtures of partially structured folding intermediates. We decided to embark on a chaperone discovery journey with the aim of finding chaperones that are simpler and more biophysically tractable than those currently studied. Ideally, these new chaperones should act on a substrate protein whose folding mechanism is already well characterized, so that we candetermine precisely how the chaperone is affecting the folding of the substrate. We thus developed genetic selections that directly link the stability of model folding proteins to increased antibiotic resistance in vivo. The folding biosensors that we have developed function in the bacterial periplasm and cytosol, and in yeast. These biosensors have allowed us to optimize protein folding and discover new chaperones we used the first of our discovered chaperones, Spy, as a model to delve deeply into chaperone biology and we now understand, in unprecedented detail, how this chaperone interacts with client proteins to facilitate their folding. We are following our chaperone discovery efforts into yeast with the aim of addressing the role that host factors play in amyloid formation, which is linked to a number of devastatingneurological diseases. James C. Bardwell, PhDRowena G. Matthews Collegiate Professor, Department of Molecular, Cellular, and Developmental BiologyProfessor, Department of Biological ChemistryUniversity of Michigan Howard Hughes Medical Institute Investigator

Oct

BMG Seminar: Immortal Hematopoietic Stem Cells and Their Regulation by DNA Methylation - Peggy Goodell, PhD

Chicago - 10:00 AM - 11:00 AM

The peripheral blood is composed of many different cell types which are constantly being replenished via hematopoietic stem cells (HSCs). When young, thousands of hematopoietic stem cells residing in the bone marrow are simultaneously regenerating the blood. Over the past few years, high throughput sequencing has revealed that as we age, one or a few stem cells start dominating blood production, resulting in a condition termed “clonal hematopoiesis”, or “CH”. CH represents blood production from “immortal” stem cells that outcompete their normal counterparts. CH is driven by somatically acquired mutations in around 20 genes which confer a selective advantage over time. The gene encoding DNA methyltransferase 3A (DNMT3A) is the most commonly mutated gene in CH, indicating that loss of its function confers longevity on the stem cell, even as it puts the host at risk for age-associated diseases such as leukemia. Dr. Goodell will discuss some of the cellular and molecular mechanisms that drive expansion of HSCs with DNMT3A and other CH-associated mutations. Peggy Goodell, PhDProfessor, Department of PediatricsProfessor, Department of Molecular and Human GeneticsVivian L. Smith Chair in Regenerative MedicineBaylor College of Medicine

Oct

BMG Seminar: Metabolic control of cell growth through the PI3K-mTOR signaling network - Brendan Manning, PhD

Chicago - 10:00 AM - 11:00 AM

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a key signaling node, universal to eukaryotic cells, which links the sensing of nutrients to the coordinated regulation of nutrient metabolism. mTORC1 has the ability to integrate signals from a variety of sources, including intracellular nutrients and secreted growth factors. The activation state of mTORC1 is tightly controlled through a small G protein switch involving the TSC1-TSC2-TBC1D7 complex (the TSC complex) and the Ras-related small G protein Rheb. The direct phosphorylation and inhibition of the TSC complex by the protein kinase Akt provides the major mechanistic link between growth factor signaling and mTORC1. Current evidence indicates that this signal is integrated with amino acid sensing pathways upstream of mTORC1 through independent spatial control over the subcellular localization of the TSC complex and mTORC1 to the surface of the lysosome. Our data indicate that both physiological growth signals and common oncogenic events in cancer activate mTORC1 through mechanisms leading to dissociation of the TSC protein complex from the lysosomal subpopulation of Rheb, which is required for mTORC1 activation. Physiological and pathological activation of PI3K-mTOR signaling results in a shift from catabolic processes to anabolic biosynthetic processes. This pathway acutely responds to feeding and is also frequently and aberrantly activated in human cancers. Through unbiased genomic and metabolomic approaches, we have found that, in addition to its established roles in promoting protein synthesis and inhibiting autophagy, mTORC1 stimulates changes in specific metabolic pathways through transcriptional and posttranslational effects on metabolic enzymes. In this manner, mTORC1 serves to link growth signals to metabolic processes that promote the growth of cells, tissues, and tumors, including the de novo synthesis of proteins, lipids, and nucleotides. Research in our lab is focused on understanding the coordinated anabolic program downstream of PI3K-mTOR signaling and identifying metabolic vulnerabilities stemming from uncontrolled pathway activation that can be targeted in tumors. I will discuss our latest data on additional metabolic enzymes under control of the PI3K-mTOR network that contribute to an integrated metabolic program underlying cell growth in both normal and cancer cells. Brendan Manning, PhDProfessor, Department of Genetics and Complex DiseasesDirector of the Division of Biological SciencesDirector of the PhD Program in Biological Sciences in Public Health, Harvard Graduate School of Arts and SciencesHarvard T.H. Chan School of Public Health

Oct

BMG Seminar: Maintaining Genome Stability During DNA Replication -David Cortez, PhD

Chicago - 10:00 AM - 11:00 AM

Billions of base pairs of DNA must be replicated trillions of times during a human lifetime. Adding to the difficulty, thousands of DNA lesions happen in each cell of our body every day. Furthermore, replication is challenged by difficult to replicate sequences and conflicts with transcription. To combat these threats, DNA damage response mechanisms act to repair the damaged DNA, signal cell cycle checkpoint activation, ensure completion of DNA replication, and maintain genome stability. Defects in these mechanisms cause developmental abnormalities, premature aging, and cancer. We have utilized a proteomic approach invented by a former graduate student called iPOND to inventory and track ~600 proteins that act at active and damaged replication forks. This approach identified proteins including ETAA1, RADX, and HMCES that act in different replication-stress response pathways. I will present our latest discoveries about how these proteins function to maintain genome stability. David Cortez, PhDProfessor, Department of BiochemistryIngram Professor of Cancer ResearchCo-Leader, Genome Maintenance Program, Vanderbilt-Ingram Cancer CenterVanderbilt University School of Medicine

Oct

BMG Journal Club

Chicago - 3:30 PM - 5:00 PM

The BMG Journal Club will convene every other Friday from 3:30pm to 5:00pm. This is an opportunity for the department to come together and have in-depth discussions about the current literature and the overall implications of new studies, enhancing everyone’s knowledge of the field at large and about each other’s research interests within the department; providing possible opportunities to collaborate as well. This is also an opportunity to practice vital presentation skills in front of a friendly audience. Pizza and soda will be served.

Oct

BMG Seminar: Setting Boundaries: How cells keep telomeres in check -Eros Lazzerini Denchi, PhD

Chicago - 10:00 AM - 11:00 AM

The Department of Biochemistry and Molecular Genetics Departmental Seminar Series presents: Eros Lazzerini Denchi, PhDInvestigator, Laboratory of Genome IntegrityNIH Stadtman InvestigatorCenter for Cancer Research, National Cancer InstituteNational Institutes of Health

Nov

BMG Seminar: Computation, Memory, and Complexity: Design of Gene Regulatory Circuits in Eukaryotic Cells - Ahmad (Mo) Khalil, PhD

Chicago - 10:00 AM - 11:00 AM

Eukaryotic organisms display diverse genetic responses to the environment. These complex responses are mediated by genetic regulatory circuits that enable cells to perform core functions, such as process signals, execute computations, and store memory. What molecular circuit designs enable these core functions, and how do regulatory circuits evolve? How do we engineer synthetic circuits to program desired cellular functionality? To address these questions, my lab primarily employs synthetic biology approaches and develops new laboratory technologies. This talk will explore eukaryotic transcriptional circuit design principles from a synthetic biology perspective. I will describe a new approach for engineering fully artificial transcriptional and epigenetic circuits that explore and exploit common natural regulatory features, such as cooperative transcription factor (TF) assembly and reading / writing chromatin modifications. In addition, I will present a highly flexible and automated, continuous culture platform we invented, called eVOLVER, that allows researchers to grow and experimentally evolve natural and synthetic cellular systems in highly defined growth conditions. Ahmad (Mo) Khalil, PhDAssistant Professor, Department of Biomedical EngineeringAssociate Director, Biological Design CenterRajen Kilachand Center for Integrated Life Sciences & EngineeringBoston University

Nov

BMG Journal Club

Chicago - 3:30 PM - 5:00 PM

Nov

CANCELLED - BMG Seminar: Sara Buhrlage, PhDBMG Seminar: Sara Buhrlage, PhD

Chicago - 10:00 AM - 11:00 AM

The Department of Biochemistry and Molecular Genetics Departmental Seminar Series presents: Sara Buhrlage, PhDAssistant Professor, Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolAssistant Professor, Cancer BiologyDana-Farber Cancer Institute

Nov

BMG Seminar: John Blenis, PhD

Chicago - 10:00 AM - 11:00 AM

The Department of Biochemistry and Molecular Genetics Departmental Seminar Series presents: John Blenis, PhD Anna Maria and Stephen Kellen Professor of Cancer ResearchProfessor, Department of PharmacologyAssociate Director of Basic Science, Sandra and Edward Meyer Cancer CenterWeill Cornell Medicine

Nov

BMG Journal Club

Chicago - 3:30 PM - 5:00 PM

Dec

BMG Seminar: Nrf2 activation promotes lung cancer metastasis by inhibiting the Fbxo22-mediated degradation of Bach1 -Michele Pagano, MD

Chicago - 10:00 AM - 11:00 AM

About 30% of lung adenocarcinomas (LUADs) increase the transcription of antioxidant genes to maintain oxidative homeostasis. This increase is made possible by mutations that stabilize Nrf2, the master transcriptional regulator of the cell’s antioxidant program. These mutations are associated with an aggressive cancer phenotype and either directly target Nfe2L2 (encoding Nrf2) or inactivate Nrf2’s negative regulator, Keap1. Keap1 is a substrate receptor of a CRL3 ubiquitin ligase complex that, in physiological conditions, constitutively targets Nrf2 for degradation. We asked whether LUADs with Keap1 mutations are more aggressive than LUADs harboring wild-type Keap1 due to an increased metastatic burden, and by which mechanism. We found that stabilization of Nrf2 in LUAD activates a pathway that in turn stabilizes Bach1, a transcription factor that controls the expression of a plethora of pro-metastatic genes. Mechanistically, mutations that stabilize Nrf2 drive the Nrf2-mediated induction of heme oxygenase 1 (Ho1), an enzyme responsible for heme catabolism. We also found that heme promotes the interaction of Bach1 with CRL1Fbxo22. Therefore, increased heme catabolism leads to a decrease in free heme, reducing the CRL1Fbxo22-mediated degradation of Bach1. Thus, in normal cells, either Nrf2 is low and Bach1 is high (under unstressed conditions) or Nrf2 is high and Bach1 is low (upon oxidative stress). Instead, LUAD cells paradoxically display high levels of both Nrf2 and Bach1, thus promoting cell survival and inducing cell migration, respectively. We extensively validated our mechanistic results in mouse models of LUAD, as well as in samples of LUAD patients. We propose that: 1) Nrf2 induces lung cancer metastases by reducing heme- and Fbxo22-mediated degradation of Bach1, which in turn activates the transcription of pro-metastatic genes; and 2) drugs targeting the heme pathway represent a promising strategy to block metastasis in LUAD patients. Moreover, we suggest that Ho1 and Bach1 could be used as LUAD biomarkers to improve the design of precision medicine approaches and clinical trials, and to monitor the response to therapy. Michele Pagano, MDChair, Department of Biochemistry and Molecular PharmacologyMay Ellen and Gerald Jay Ritter Professor of Oncology, Department of Biochemistry and Molecular PharmacologyNew York University School of MedicineHoward Hughes Medical Institute Investigator