Seminar on Bioinformatics & Bioengineering

April 2 – Jeremy Sanford, UCSC: “RISCy business: Modulation of a malignant RNA regulon by the oncofetal RNA binding protein IGF2BP3”

 The Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is overexpressed in a diverse array of cancers but its regulatory targets and role in pathogenesis are poorly understood. We applied a combination of high throughput approaches including individual-nucleotide resolution crosslinking immunoprecipitation (iCLIP), RNA immunoprecipitation (RIP) and gene expression profiling to determine the regulatory landscape of IGF2BP3 in pancreatic ductal adenocarcinoma (PDAC) cell models and pre-B cell acute lymphoblastic leukemia. These experiments defined target transcripts with roles in cancer cell biology as well as a strong enrichment for binding sites within 3’ untranslated regions (3’UTRs). The RNA map also revealed significant sequence similarity and positional overlap of IGF2BP3 binding sites and cancer-related microRNA target sites. Furthermore, depletion of IGF2BP3 from PDAC cells alters the steady state levels of target transcripts, their association with the RNA induced silencing complex (RISC) and mRNA sedimentation in sucrose gradients.  Taken together these results suggest that IGF2BP3 promotes a malignant gene expression program by modulating microRNA-mediated gene regulation.

 

April 9 – Jason Cyster, UCSF: "Deciphering the guidance cue code for B cell immunity”

During immune responses, immune cells undergo a tightly choreographed series of movements that guide them between supportive niches. As part of our effort to comprehensively characterize the cues guiding each step of activated B cell movement we identified a role for EBI2 (GPR183). In collaboration with a team at Novartis, we established that the oxysterol, 7a,25-dihydroxycholesterol (7a,25-HC) is an EBI2 ligand and novel guidance factor for activated B cells. We then established the enzyme distribution pattern needed for generation of B cell guiding 7a,25-HC gradients and showed this cue is also involved in controlling dendritic cell movements. Our work on the enzyme requirements for 7a,25-HC production led us to find that the precursor sterol, 25-HC, plays an important role downstream of type I IFN in mediating feedback regulation of IL1-family cytokine production.

 

April 16 - Julie Zikherman, UCSF: “Shaping the B cell repertoire in health and disease”

Our laboratory is interested in understanding how the normal repertoire of B cell antigen receptors is established and controlled during B cell development and how this process is disrupted in autoimmune disease. To do so, we are taking advantage of novel reporter mice in which autoreactive B cells are fluorescently marked. We are combining these reporters with receptor cloning, transcriptome profiling, biochemical analysis of signal transduction, and genetic mouse models in order to dissect how autoreactivity is selected and counterselected in the mature B cell repertoire, and how potentially autoreactive B cells are normally restrained.

 

April 23 – Ahmet Ali Yanik, UCSC: "Optofluidic BioNEMS: Lab-on-Chip Devices for Infectious Disease and Cancer Diagnostics"

Nanophotonics is opening a myriad of unprecedented opportunities for biomedical applications by localizing light beyond the diffraction limit and dramatically boosting the light-matter interactions at nanoscale dimensions. In this talk, I will introduce a number of transformative technologies based on nanoscale control of light and fluidics on a chip. I will show how to overcome some of the fundamental limitations of the state of art techniques used in vitro diagnostics of infectious diseases and cancer.

Host: Nader Pourmand

  

April 30 – Matthew Krummel, UCSF: "Imaging the Immune Response to Tumors”

 

May 7 – Katja Brückner, UCSF: "An inducible signal from sensory neurons regulated adaptation of the blood cell pool in Drosophila"

 

May 14 – Jeffrey Bush, UCSF: "Eph/ephrin signaling in morphogenesis and congenital disease”

Our lab studies the cellular and molecular basis for morphogenesis relevant to human congenital disease, with a particular focus on craniofacial disease, using mouse genetic and cell biological methodologies. The Eph receptor tyrosine kinases and their signaling partners the ephrins are critical regulators of many aspects of development, including craniofacial development. They can facilitate the self-organization of tissues by cell segregation mediated by cell adhesion and cell repulsion behaviors. I will discuss our studies of Eph/ephrin signaling mechanisms and their control of cell behavior and how these contribute to structural birth defects.

 

May 21 – Scott Dylla, StemCentRx: "Discovery & Development of an Antibody-Drug Conjugate that Effectively Targets Triple-Negative Breast and Ovarian Tumor-Initiating Cells to Result in Sustained Tumor Regressions"

Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival. We herein identified CD324 as a surface antigen able to reproducibly enrich for TIC in well annotated, low passage TNBC and ovarian cancer patient-derived xenografts (PDXs). Gene expression analysis of TIC led to the identification of a prospective therapeutic target. An antibody-drug conjugate (ADC) developed against this target achieved sustained tumor regressions in both TNBC and ovarian cancer PDX tumor models in vivo. Non-claudin low TNBC tumors exhibited higher expression and more robust responses than other breast cancer subtypes, suggesting a specific translational application for tumor sub-classification. These findings demonstrate the potential of this ADC as a first-in-class compound designed to eradicate TIC.

 

May 28 – Russ Corbett, UC Berkeley: "Next-Generation Population Genomics: Inversion Polymorphisms, Epistasis, and the Paradox of Variation”

Although many fundamental questions in evolutionary genetics have been theoretically well posed for decades, until recently relatively little data on natural genetic variation has been available for direct hypothesis testing. Next-generation sequencing is rapidly changing that. Hence data analysis and interpretation has become the central challenge of population genetics. Within that vein, I will present my work developing population genomic and bioinformatics methods to study three central, longstanding questions in population genetics. (1) The detection and evolutionary impacts of chromosomal inversions. (2) The evolution and phenotypic consequence of gene-gene interactions—epistasis—within populations. (3) The impact of natural selection in shaping patterns of genetic variation across a wide variety of species.

Host: Ed Green

 

June 4 – Sofie Salama, UCSC: “An evolutionary arms race between KZNF transcription factors and retrotransposons drives genome complexity”

Throughout evolution our genome has been modified by waves of retrotransposon insertions. For each wave, the host eventually finds a way to repress retrotransposon transcription and prevent further insertions. We determined the mechanism by which this is achieved for two classes of retrotransposons active in the primate lineage. In each case, a primate-specific KRAB Zinc Finger transcription factor rapidly evolved to repress a specific class of retrotransposon shortly after it began to spread in our ancestral genome. We also found that the binding of these KZNFs to retroelements in our genome affects the expression of nearby genes suggesting that together they provide a source of material for the evolution of new regulatory networks.

Host: Sofie Salama

Instructors and Assistants