Biochemistry and Molecular Biophysics Graduate Group

BMB Home » Faculty » By Research Interest

pixel Control of Gene Expression and Cellular Programming

Joseph A. Baur, Ph.D.

Molecular mechanisms of aging and caloric restriction

Assistant Professor of Physiology
12-114 Smilow Center for Translational Research
Tel: 215-746-4585 / Fax: 215-898-5408
Email: baur@mail.med.upenn.edu

The Baur lab is interested in the basic mechanisms that lead to aging. Age is the most important risk factor for many of the diseases affecting Western society today, including cancer, cardiovascular disease, and neurodegenerative disorders.

Shelley L. Berger, Ph.D.

Role of adaptors in regulation of transcriptional activation in yeast and humans

Daniel S. Och University Professor
Department of Cell & Developmental Biology
9-125 Smilow Center for Translational Research
Tel: 215-746-3106 (office) / Fax: 215-746-8791
Email: bergers@upenn.edu
Berger Cell & Dev Bio page

Our research focuses on regulation of the nuclear genome in mammals and model organisms. The long strands of nuclear DNA are associated with packaging proteins, called histones, into a structure known as chromatin, akin to the way thread is organized around a spool. We are particularly interested in changes in this chromatin structure via chemical modification of the histone proteins, and how attachment of certain chemical groups onto the histones leads to altered chromatin function. These targeted structural changes are conceptually like the unraveling of the thread to reach specific, buried sections. We are also fascinated by functional changes in chromatin, caused by these histone modifications, that persist through cell division from one cell into two daughter cells; these persistent, or epigenetic, changes are of particular interest because they are key to normal and abnormal growth: they occur during organismal development into multicellular tissues and organs, and are typically disrupted during abnormal reversal of tissue specialization and growth control as in cancer, as well as during aging of cells and individuals. 

Lawrence Brass, M.D., Ph.D.

Molecular basis for intracellular signaling in vascular biology

Professor of Medicine, Pathology & Laboratory Medicine, and Pharmacology
Associate Dean and Director, Combined Degree and Physician Scholar Program School of Medicine
913 Biomedical Research Building II/III
Tel: 215-573-3540 / Fax: 215-573-2189
Email: brass@mail.med.upenn.edu

Combined Degree Program

Most of the work we are currently doing is devoted to understanding the molecular basis for platelet activation in vivo. Individual projects are looking at the role of heterotrimeric G proteins in initiating platelet activation, low molecular weight GTP-binding proteins in fostering integrin activation, and Eph kinases in maintaining platelet activation. The actual studies are being done in vitro using isolated human platelets and transfected cell systems, and in vivo using genetically engineered mice.

 

Sara Cherry, Ph.D.

Genetic and mechanistic studies of viral-host interactions

Assistant Professor of Microbiology
304K Lynch Laboratories
433 South University Avenue
Tel: 215-746-2384 /Fax: 215-746-6697
Email: cherrys@mail.med.upenn.edu
Cherry Departmental Page

Research in the Cherry lab is aimed at identifying cellular factors that regulate viral pathogenesis, including both those factors hijacked by viruses for replication and those innate anti-viral mechanisms used by the host to combat the invader. To identify these factors we are taking a genetic approach by screening for factors that impact viral replication. To this end, we are using the model genetic organism Drosophila. This allows us to use a wide-variety of techniques to identify these genes including both high-throughput RNA interference screens in cell culture, and forward genetic screens in animals. Moreover, we are also screening for host factors in human cells using high-throughput RNA interference screening technologies. We are using these approaches to study a number of arthropod-borne RNA viruses, including the flavivirus West Nile virus, the alphavirus Sindbis and the bunyavirus Rift Valley Fever virus. These are the three major families of viruses that are important human pathogens transmitted by mosquitoes to humans. By screening in both hosts- insect and human- we hope to gain a more comprehensive understanding of the host factor requirements of these pathogens. We are currently characterizing the roles of candidate genes already uncovered by using molecular biological and cell biological techniques and have discovered factors involved in viral replication and innate immunity. By combining these methodologies, and using a variety of viruses, we hope to gain a comprehensive understanding of the interplay between the host and pathogen in a complex and dynamic setting. Taking advantage of forward genetics and functional genomics in will allow us to use these unbiased and global methodologies to identify many important and novel host factors that modulate virus-host interactions. Moreover, the more viral-host pairs that we study, the better our understanding of pathways and processes essential to pathogens, and the more equipped we will be to develop anti-viral treatments.

 

Gideon Dreyfuss, Ph.D.

Nuclear transport, hnRNP complexes, RNA-binding proteins, spinal muscular atrophy

Isaac Norris Professor of Biochemistry & Biophysics
Howard Hughes Medical Institute Investigator
328 Clinical Research Building
Tel: 215-898-0398, 215-898-0172 / Fax: 215-573-2000
Email: gdreyfuss@hhmi.upenn.edu
Dreyfuss Lab Homepage / Dreyfuss Departmental Page / Howard Hughes Medical Institute Page

The research efforts of the Dreyfuss laboratory are presently focused on four interrelated topics:

  1. The transport of proteins and RNAs between the nucleus and the cytoplasm
  2. The molecular function of SMN (Survival of Motor Neurons), the protein product of the Spinal Muscular Atrophy (SMA) disease gene
  3. The structure and function of the hnRNP proteins, with particular focus on the role of these proteins in the formation and function of mRNA
  4. Novel phage display methods for identification of interacting proteins.

 

Hua-Ying Fan, Ph.D.

Regulation of chromatin structure and its impact on human diseases

Assistant Professor of Biochemistry & Biophysics
9-133 Smilow Center for Translational Research
Tel: 215 573-5705 (office)
Email: hfan@mail.med.upenn.edu

The Fan lab is interested in understanding the mechanisms of epigenetic regulation. Epigenetics describes the process by which a specific transcriptional program, induced by a signal, is maintained and inherited through cell divisions without the necessary presence of the original signal. Chromatin structure holds the secrets of epigenetic regulation. To dissect the mechanisms of epigenetic regulation, our research is focused in two main directions. First, we study how ATP-dependent chromatin remodelers regulate chromatin structure and how defects in these activities can lead to disease. Currently, we are using CSB (Cockayne Syndrome complementation group B) as a model protein to understand the function of ATP-dependent chromatin remodeling in DNA repair, aging and cancer. Second, we wish to understand how epigenetic regulatory mechanisms influence cancer cell self-renewal and differentiation, mechanisms that might impact the programming and reprogramming capacity of cancer cells. Results from our studies will, therefore, not only shed light on fundamental mechanism of epigenetic regulation, but will provide novel insights into the causes and mechanisms of disease.

 

Ekaterina L. Grishchuk, Ph.D.

Mechanisms that drive and control chromosome motions in mitosis

Assistant Professor of Physiology
A401 Richards Building
Office: (215) 746-8178 / Fax: (215) 573-2273
Email: gekate@mail.med.upenn.edu

Rahul M. Kohli, M.D., Ph.D.

Investigating the enzymatic basis for diversity generation in the immune system and pathogens; enzyme mechanisms, chemical biology, protein evolution

Assistant Professor of Medicine, and Biochemistry & Biophysics
502B Johnson Pavilion
Tel: 215-662-2359 / Fax: 215-349-5111
Lab: 509 Johnson Pavilion / Tel: 215-614-0163
Email: rkohli@mail.med.upenn.edu

Our laboratory focuses on the enzymatic generation of genomic diversity. We utilize a broad array of approaches, including biochemical characterization of enzyme mechanisms, chemical synthesis of enzyme probes, and biological assays spanning immunology and virology to study this central tactic in the constant battle between our immune system and pathogens.

From the host immune perspective, the generation of genomic diversity is used as both a defensive and an offensive weapon. On the one hand, host mutator enzymes such as Activation-Induced Cytidine Deaminase (AID) seed diversity in the adaptive immune system by introducing targeted mutations into the immunoglobulin locus that result in high affinity antibodies (somatic hypermutation) or altered isotypes (class switch recombination). Related deaminases of the innate immune system can directly attack retroviral threats by garbling the pathogen genome through mutation, as accomplished by the deaminase APOBEC3G, which restricts infection with HIV. Immune mutator enzymes, however, also pose a risk to the host, as overexpression or dysregulation have been associated with oncogenesis.

From the pathogen perspective, alteration in key antigenic determinants at a rate that outpaces immune responses is a potent means for evasion. Further, rapid mutation may allow for the development of resistance to antimicrobials.

Our research program aims to understand mutator enzymes and pathways in the immune system and pathogens. We further aim to harness these diversity-generating systems for directed evolution of proteins. Additionally, we apply chemical biology to decipher and target these pathways, to impede the development of multidrug-resistance in pathogens or prevent the neoplastic transformations that can result from genomic mutation.

 

 


 

Mitchell Lewis, D.Phil.

Gene regulation; protein crystallography; structural basis of recognition

John Morgan Professor of Biomedical Research and Education
Department of Biochemistry & Biophysics
813B Stellar-Chance Labs
Tel: 215-898-0711 (lab) 215-898-0949 (office)
Email: lewis@mail.med.upenn.edu
Lewis Departmental Page

The major objective of our research is to understand how proteins respond to metabolites and regulate transcription. Our work has focused on the repressor of bacteriophage lambda and the lac operon of E. coli. For almost half a century, these two systems have served as the paradigm for understanding gene regulation. The primary focus of our lab has been to provide detailed structural information on these two systems.

 

Kristen W. Lynch, Ph.D.

Mechanism and consequences of regulated alternative splicing

Associate Professor of Biochemistry & Biophysics, and Genetics
909B Stellar-Chance Labs
Tel: 215-573-7749 (office); 215-573-7756 (lab)
email: klync@mail.med.upenn.edu
Lynch Lab

Recent insight into the human genome has revealed that most genes encode multiple distinct protein isoforms through the process of alternative pre-mRNA splicing. My laboratory is focused on understanding the biochemical mechanisms and regulatory networks that control alternative splicing in response to antigen-challenge of the human immune system. Recently we have identified ~150 genes that exhibit an alteration in isoform expression in response to T cell stimulation. Through our initial work on the regulated splicing of the protein tyrosine phosphatase CD45, we have identified the regulatory sequence, proteins that controls activation-induced isoform expression of CD45 as well as exons in several other genes essential for T cell function. This work is on-going as we seek to understand the mechanism of this regulation at molecular and atomic detail. We are also expanding our focus to include additional networks of co-regulated splicing events in T cells. Together these studies are providing new insights into the mechanisms and consequences of RNA-based gene regulation in the cellular response to environmental stimuli.

 

Ronen Marmorstein, Ph.D.

X-ray crystallography, chromatin regulation, tumor suppressors, oncoproteins, kinases, aging, structure-based inhibitor design

Professor of Biochemistry and Biophysics
454 Biomedical Research Building II/III
Tel: 215-898-7740 / Fax: 215-746-5511
Email: marmor@mail.med.upenn.edu

The laboratory uses a broad range of molecular, biochemical and biophysical research tools centered on X-ray crystal structure determination to understand the mechanism of macromolecular recognition and post-translational histone and protein modifications in the regulation of gene expression, chromatin and epigenetics. The laboratory is particularly interested in gene regulatory proteins and kinases that are aberrantly regulated in cancer and age-related metabolic disorders such as type II diabetes and obesity, and the use of high-throughput small molecule screening and structure-based design strategies towards the develop protein-specific small-molecule compounds to treat such diseases.

 

John I Murray, Ph.D.

Embryonic transcriptional regulation; fate specification; cell lineages; C. elegans; microscopy

Assistant Professor of Genetics
Ph.D. 2004, Stanford University (Genetics)
437A Clinical Research Building
Tel: 215-746-4387 / Fax: 215-746-6258
Email: jmurr@mail.med.upenn.edu
Murray Departmental Page

 

Hillary C.M. Nelson, Ph.D.

Structural biology; transcription; protein-DNA interactions; heat shock response

Associate Professor of Biochemistry & Biophysics
813A Stellar-Chance Labs
Tel: 215-573-7473
Email: hnelson@mail.med.upenn.edu
Nelson Departmental Page

 

Arjun Raj, Ph.D.

Systems biology; developmental biology; non-coding RNA

Assistant Professor of Bioengineering
Skirkanich Hall, Room 240
Email: arjunraj@seas.upenn.edu
Website: http://rajlab.seas.upenn.edu/

The Raj lab studies the biology of single cells. The primary motivation for studying biological processes on a cell-by-cell basis is the fact that even genetically identical cells can behave very differently. Many of these differences arise as a consequence of the developmental process, whereby some cells are directed to become, for example, liver cells while others become skin cells. We aim to understand these differences at the molecular level. One of our primary experimental tools is a method we have developed for detecting individual RNA molecules via fluorescence microscopy, yielding very precise, quantitative data about RNA abundance and localization within single cells. One application of this method is the visualization of non-coding RNAs. Recently, researchers have made the exciting discovery that much of the genetic material that was previously thought to be “junk” DNA is actually converted into RNA molecules, and some of these non-coding RNA molecules appear to have direct functional roles in development. We are directly visualizing and localizing these molecules in their cellular context to decipher the mechanisms by which they operate, including potential roles in stem cell differentiation. Another area in which cellular heterogeneity is important is cancer. We are producing RNA expression maps throughout tumor sections at single cell resolution to measure spatial variation in expression during tumor formation and development. We anticipate that such studies will lead to new diagnostic tools as well as a deeper understanding of cancer biology.

 

James Shorter, Ph.D.

Regulation of beneficial or neuropathogenic prions and amyloids by protein-remodeling factors, molecular chaperones, and small molecules

Associate Professor of Biochemistry & Biophysics
805B Stellar-Chance Labs
Tel: 215-573-4256 (office) / 215-573-4257 (lab)
Email: jshorter@mail.med.upenn.edu
Shorter Lab website / Shorter Departmental Page
Read about Dr. Shorter's NIH Director's New Innovator Award (October 2007)

Life demands that proteins fold into elaborate structures to perform the overwhelming majority of biological functions. We investigate how cells achieve such successful protein folding. In particular, we seek to understand how cells prevent, reverse, or even promote the formation of prion and amyloid fibers.

 

David Speicher, Ph.D. 

Cancer proteomics; structure-function of membrane associated proteins: protein chemistry and mass spectrometry

Wistar Institute Professor of Biochemistry & Biophysics
151 Wistar Institute
Tel: 215-898-3972
Fax: 215-898-0664
Email: speicher@wistar.org

Our research group primarily focuses on proteomics of human diseases and structure-function of protein-protein interactions. We are currently pursuing two structure-function projects that primarily utilize biophysical methods, such as isothermal titration calorimetry and sedimentation equilibrium, and mass spectrometry to probe protein structures, protein-protein interactions and function. One project involves the giant membrane skeletal protein spectrin, a human actin crosslinking protein that plays a key role in stabilizing the plasma membrane in most cell types. Current studies focus on the proteotypical spectrin tetramers found in human red blood cells and their role in membrane purturbations caused by hereditary hemolytic anemia mutations. Another project involves structure-function analysis of peroxiredoxin 6, an antioxidant enzyme with glutathione peroxidase activity and phospholipase activity, which plays a critical role in protecting lung and other tissues from damage due to oxidative stress

 

Gregory D. Van Duyne, Ph.D.

Structural biology; protein-protein interactions; x-ray crystallography

Jacob Gershon-Cohen Professor of Medical Science
Department of Biochemistry & Biophysics
809B Stellar-Chance Labs
Tel: 215-898-3058
Fax: 215-573-4764
E-mail: vanduyne@mail.med.upenn.edu
Van Duyne Departmental Page

We are interested in understanding on a structural and biochemical level how DNA and RNA molecules are maintained and processed by living cells. In addition to the mechanisms and regulation of genome replication and transcription, this includes processes such as DNA repair, site-specific and homologous recombination, transposition, condensation of chromosomes, chromosome pairing and segregation, and RNA trafficking and splicing. Our approach is to establish three-dimensional models of macromolecular assemblies relating to a particular biological question using X-ray diffraction methods and to then develop mechanistic and functional models that can be tested experimentally.

 

Kathryn E. Wellen, Ph.D.

Cancer cell metabolism, nutrient sensing

 

Assistant Professor of Cancer Biology
611 Biomedical Research Building II/III
Tel: 215-746-8599 (office); 215-746-4956 (lab)
Fax: 215-573-6725
E-mail: wellenk@exchange.upenn.edu
Wellen Departmental Page

Our laboratory is interested in understanding how nutrient metabolism interfaces with signaling and transcriptional networks, with a current focus on metabolic regulation of the epigenome. Diseases such as cancer and diabetes are characterized by significant epigenetic and cell metabolic alterations. Chromatin modifications such as histone acetylation are sensitive to changes in nutrient metabolism, although the contribution of metabolism to epigenetic regulation in normal physiology or in disease states is not known. Current goals of our research include defining the molecular mechanisms that link cellular metabolism to the epigenome and investigating the functional significance of this interaction in cancer and metabolic diseases.

 

Jeremy E. Wilusz, Ph.D.

Regulation of noncoding RNA biogenesis and function

Assistant Professor of Bichemistry & Biophysics
363 Clinical Research Building
Ph.D., 2009, Cold Spring Harbor Laboratory (Biological Sciences)
Tel: 215-898-8862
E-mail: wilusz@mail.med.upenn.edu

The sequencing of the human genome provided quite a surprise to many when it was determined that there are only ~20,000 protein-coding genes, representing less than 2% of the total genomic sequence. Since other less complex eukaryotes like the nematode C. elegans have a very similar number of genes, it quickly became clear that the developmental and physiological complexity of humans probably can not be solely explained by proteins. We now know that most of the human genome is transcribed, yielding a complex repertoire of RNAs that includes tens of thousands of individual noncoding RNAs with little or no protein-coding capacity. Among these are well-studied small RNAs, such as microRNAs, as well as many other classes of small and long transcripts whose functions and mechanisms of biogenesis are less clear – but likely no less important. This is because many of these poorly characterized RNAs exhibit cell type-specific expression or are associated with human diseases, including cancer and neurological disorders. Our goal is to characterize the mechanisms by which noncoding RNAs are generated, regulated, and function, thereby revealing novel fundamental insights into RNA biology and developing new methods to treat diseases.

Much of our work has focused on the MALAT1 locus, which is over-expressed in many human cancers and produces a long nuclear-retained noncoding RNA as well as a tRNA-like cytoplasmic small RNA (known as mascRNA). Despite being an RNA polymerase II transcript, the 3’ end of MALAT1 is produced not by canonical cleavage/polyadenylation but instead by recognition and cleavage of the tRNA-like structure by RNase P. Mature MALAT1 thus lacks a poly(A) tail yet is expressed at a level higher than many protein-coding genes in vivo. We recently showed that the 3’ end of MALAT1 is protected from 3’-5’ exonucleases by a highly conserved triple helical structure. Surprisingly, when this structure is placed downstream from an open reading frame, the transcript is efficiently translated in vivo despite the lack of a poly(A) tail. This result challenges the common paradigm that long poly(A) tails are required for efficient protein synthesis and suggests that non-polyadenylated RNAs may produce functional peptides in vivo via mechanisms that are likely independent of poly(A) binding protein. To address these issues, we are currently elucidating the molecular mechanism by which a triple helix functions as a translational enhancer. In addition, we are developing approaches to identify additional triple helices that form across the transcriptome, thereby revealing new paradigms for how RNA structures regulate gene expression.

Besides MALAT1, only a handful of long RNA polymerase II transcripts (e.g. histone mRNAs) have been clearly shown to be processed at their 3’ ends via non-canonical mechanisms. This is likely because nearly all previous studies characterizing the transcriptome have focused only on polyadenylated RNAs, thereby missing RNAs that lack a poly(A) tail. Nevertheless, it is becoming increasingly clear that non-polyadenylated RNAs are much more common and play significantly greater regulatory roles in vivo than previously appreciated. For example, an abundant class of circular RNAs has recently been identified in human and mouse cells. Two of these circular RNAs clearly function as microRNA sponges, but it is largely unknown why all the other circular RNAs are produced or how the splicing machinery selects certain regions of the genome (and not others) to circularize. We aim to identify and characterize additional RNAs whose 3’ ends are generated via unexpected mechanisms, thereby revealing novel paradigms for how RNAs are processed and, most importantly, new classes of noncoding RNAs with important biological functions.


 

John H. Wolfe, V.M.D., Ph.D.

Glycoproteins; lysosomal enzymes; storage diseases; gene transfer into brain

Professor of Pathology & Medical Genetics
Director of Walter Flato Goodman Center for Comparative Medical Genetics,
School of Veterinary Medicine and Stokes Institute, Children's Hospital of Philadelphia
502G Abramson Building (CHOP)
Tel: 215-590-7028 (office) / 215-590-7029 (lab) / Fax: 215-590-3779
Email: jhwolfe@vet.upenn.edu

Dr. Wolfe’s laboratory studies gene transfer and neural stem cells in the brain. Two general approaches for transferring genes to the brain are being investigated: 1) Direct transduction of brain cells in vivo is studied using vectors derived from herpesvirus (HSV), adeno-associated virus (AAV), and lentiviruses; and 2) Ex vivo gene transfer is being studied using lentiviral vectors and neural stem cells for specific properties of repopulation after transplantation.  Efforts are also directed toward understanding of the molecular and cellular mechanisms of brain cell dysfunction leading to the deficits in mentation. These studies include: 1) Gene expression array and proteomic analyses in subregions of the brain in animal models; and 2) Development of induced pluripotent stem cells from human patients, which allow analysis of diseased and control human neural cells that otherwise could not be done. 

Areas of current research include: 1) fate of viral vectors in different neuronal pathways; 2) molecular determinants of viral surface proteins affecting gene distribution; 3) biochemical properties of engineered therapeutic proteins in neurons; 4) engineering neural stem cells to improve bio-distribution; 5) development of imaging methods to monitor gene expression in vivo; 6) functional changes in disease and responses to therapy; 7) genomics and proteomics analysis of cellular changes in disease; 8) translational research to evaluate barriers to scaling up treatments to large mammalian brains.