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
Baur lab website

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; Epigenetics website

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.

 

Maya Capelson, Ph.D.

Nuclear organization of chromatin and its role in gene regulation and cell differentiation

Assistant Professor of Cell & Developmental Biology
9-101 Smilow Center for Translational Research
Tel: 215-898-0550 (office) / 215-573-7548 (lab)
Email: capelson@mail.med.upenn.edu
Capelson lab website

We are interested in how the genome is organized inside the nucleus, and how this organization contributes to functional regulation of gene activity. Spatial organization is mediated by interactions between specific regions of the genome and protein components of nuclear structural scaffolds, such as the nuclear envelope. Entire chromosomes, large chromatin domains and specific genes have been reported to occupy particular places in the nuclear three-dimensional space, in a manner that is correlated with their expression status. Such organization represents a potentially widespread mechanism of gene regulation since specifying the relative position of the DNA template inside the nucleus could influence the probability or kinetics of all possible reactions that are carried out on that template, such as transcription, silencing or replication. Yet many of the basic principles of how particular genomic loci are targeted to and affected by distinct nuclear scaffolds remain obscure. Our goal is to understand how these interactions are determined, how they can change in development or disease states, and how they influence the establishment and inheritance of gene expression patterns.

Sara Cherry, Ph.D.

Genetic and mechanistic studies of viral-host interactions

Associate 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, and Genetics
9-133 Smilow Center for Translational Research
Tel: 215 573-5705 (office)
Email: hfan@mail.med.upenn.edu
Fan Department page

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.

 

Benjamin Garcia, Ph.D.

Quantitative proteomics for analysis of chromatin structure and function

Presidental Associate Professor of Biochemistry & Biophysics
9-124 Smilov Center for Translational Research
Tel: 215-573-9423 (office) /215-573-9422 (lab)
Email: bgarci@mail.med.upenn.edu
Garcia Department page


Ekaterina L. Grishchuk, Ph.D.

Mechanisms that drive and control chromosome motions in mitosis

Assistant Professor of Physiology
675 Clinical Research Building
Office: (215) 746-8178 / Fax: (215) 573-2273
Email: gekate@mail.med.upenn.edu
Grishchuk lab website


Our goal is to understand the molecular mechanisms that produce force and accuracy for mitotic chromosome motions during cell division. With biophysical, cell biological and computational approaches we study the specialized protein complexes, which function as efficient nanomachines capable of providing durable attachments between chromosomal kinetochores and the assembling and disassembling ends of microtubules. There are no man-made or natural macro-devices that function analogously to these coupling protein complexes, so uncovering the corresponding mechanisms is both challenging and exciting. Current research is focused on kinesin motor CENP-E and the microtubule-binding protein complex Ndc80, which are studied with Total Internal Reflection Fluorescent microscopy and advanced laser trapping techniques. Rigorous understanding of how the kinetochores attach to the dynamic microtubule ends should ultimately assist developing novel and more specific anticancer drugs.

F. Bradley Johnson, M.D., Ph.D.

Telomeres, chromatin, DNA repair and their interface with cell senescence and aging.

Associate Professor of Pathology & Laboratory Medicine
402 Stellar-Chance Labs
Tel:215-573-5037 / Fax: 215-573-6317
Email: johnsonb@mail.med.upenn.edu
Johnson ITMAT website

Our lab is interested in the biology of human aging and cancer, and we are focusing particularly on how they are influenced by telomere maintenance and dysfunction. Telomeres are the structures that cap the ends of chromosomes, and this location makes them critical for genome stability as well as particularly susceptible themselves to a variety of insults including oxidative damage, exonucleolytic attack, and inappropriate processing by recombination factors.

Our lab focuses on four areas: 1) investigating mechanisms of telomere maintenance; 2) investigating the biology of G-quadruplexes, which are four-stranded DNA structures formed by G-rich sequences like telomeres; 3) using a mouse model lacking telomerase to learn more about the mechanisms by which telomere dysfunction contributes to age-related pathology; and 4) measuring in human clinical specimens of telomere lengths and capping, telomerase activity, chromatin regulators, and cell senescence.

 

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
Kohli lab website

While we conventionally think of genomic DNA as a simple polymer of A's, C's, G's, and T's, the chemistry of the genome is in fact far more interesting. Our laboratory focuses on the DNA modifying enzymes that provide an added layer of complexity to the genome. These enzymes can be involved in the purposeful introduction of mutations or in the chemical modification of nucleobases, making DNA into a remarkably dynamic entity. Many of these processes are at the heart of the battle between the immune system and pathogens. We utilize a broad array of approaches, which include 1) biochemical characterization of enzyme mechanisms, 2) chemical synthesis of enzyme probes, and 3) biological assays spanning bacteriology, immunology, and virology to study DNA modifying enzymes. Our research program aims to understand, harness and perturb these diversity generating pathways.

 

MItchell A. Lazar, M.D., Ph.D.

Sylvan Eisman Professor of Medicine
Chief, Division of Endocrinology, Diabetes, and Metabolism
Director, Institute for Diabetes, Obesity, and Metabolism a
12-102 Smilow Center for Translational Research
Tel: : 215-898-0198
Email: lazar@mail.med.upenn.edu
Lazar lab website

The Lazar laboratory is studying the transcriptional and epigenomic regulation of metabolism. We are particularly focused on the role played by nuclear receptors (NRs). In the absence of ligand, NRs bind to DNA and function as potent transcriptional repressors by recruiting corepressor complexes that include the chromatin modulating enzyme histone deacetylase 3 (HDAC3). We are studying the tissue-specific and physiological roles of the corepressor complexes using by combining genomic, genetic, proteomic, and bioinformatics, and metabolic phenotyping approaches. We are especially interested in the circadian NR Rev-erb alpha, which utilizes the corepressor complex to potently repress transcription. Rev-erb alpha is a key repressive component of the circadian clock that senses heme levels to coordinate metabolism and biological rhythms. We are also studying PPAR gamma, a nuclear receptor that is a master regulator of adipocyte (fat cell) differentiation. Ligands for PPAR gamma have potent antidiabetic activity, and thus PPAR gamma represents a key transcriptional link between obesity and diabetes. The molecular, cellular, and integrative biology of these factors are being studied in mouse and human cell lines as well as in mouse knockin and knockout models. We also have discovered resistin, a novel hormone and target of PPAR gamma that is made and secreted by fat cells in rodents and by macrophages in humans. We have demonstrated that resistin regulates insulin responsiveness, and are now using mice humanized for resistin to test the hypothesis that resistin links metabolism to inflammation in human metabolic diseases.

Nuclear receptors and the transcriptional regulation of metabolism

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

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 & Biophysics
454 Biomedical Research Building II/III
Tel: 215-898-7740 / Fax: 215-746-5511
Email: marmor@mail.med.upenn.edu
Marmorstein department website

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
437A Clinical Research Building
Tel: 215-746-4387 / Fax: 215-746-6258
Email: jmurr@mail.med.upenn.edu
Murray Departmental Page

The goal of the Murray lab is to understand how genomes encode diverse gene expression patterns and cellular phenotypes. While the genetic code provides a basis for predicting the phenotypic consequences of coding sequence changes, we don’t have an equivalent framework for regulatory sequences. The regulatory code is clearly more complex than the genetic code because it uses combinatorial protein-DNA binding rather than base pairing to achieve specificity. Because there are many regulatory proteins and DNA binding sites, unraveling the importance of each interaction will be challenging.

 

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 Department 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

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
Caspar Wistar Professor in Computational and Systems Biology
151 Wistar Institute
Tel: 215-898-3972
Fax: 215-898-0664
Email: speicher@wistar.org
Speicher lab website

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 Biochemistry & Biophysics
363 Clinical Research Building
Tel: 215-898-8862
E-mail: wilusz@mail.med.upenn.edu
Wilusz department website

Most of the eukaryotic genome is transcribed, yielding a complex repertoire of RNAs that includes tens of thousands of noncoding RNAs with little or no predicted 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. Our goal is to characterize the mechanisms by which these poorly characterized noncoding RNAs are generated, regulated, and function, thereby revealing novel insights into RNA biology and developing new methods to treat diseases. Our current efforts are two-fold. First, we are continuing to characterize the MALAT1 locus, which is over-expressed in many human cancers and produces a long nuclear-retained noncoding RNA. Despite being an RNA polymerase II transcript, the 3’ end of MALAT1 is produced by recognition and cleavage of a tRNA-like structure by RNase P. Mature MALAT1 thus lacks a poly(A) tail, yet is protected from 3’-5’ exonucleases by a highly conserved triple helical structure. Second, we are studying the mechanism by which circular RNAs are produced and function. These circular transcripts are generated from protein-coding genes via an unusual pre-mRNA splicing reaction, yet it is largely unclear why the splicing machinery selects certain regions of the genome (and not others) to circularize.


 

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
Wolfe lab website

Animal homologs of human genetic diseases are used as test systems for gene transfer by viral vectors or stem cell therapies focused on the central nervous system. The include ex vivo gene transfer using genetically modified neural stem cells and direct injection of herpes, adeno-associated and lentivirus vectors. The studies involve transport within neural systems of proteins and/or vectors, properties of transduction for different cell types and various subregions of the brain, modification of therapeutic proteins for improved bioavailability, gene and protein array analysis of mechanisms of pathology and as biomarkers for pathology and response to therapies, stem cell development including diseased human iPSCs, and MRI and PET strategies for non-invasive monitoring of therapies.

 

Kenneth S. Zaret, Ph.D.

Investigating transcription factor interactions with chromatin

Joseph Leidy Professor, Department of Cell and Developmental Biology
9-131 Smilow Center for Translational Research
502G Abramson Building (CHOP)
Tel: 215-573-5813 (office) / 215-573-5844 (lab) / Fax: 215-898-9871
Email: zaret@upenn.edu
Zaret lab

The goal of Dr. Zaret's laboratory is to understand how genes are activated and different cell types are specified in embryonic development. These processes involve regulatory mechanisms that are used later in life to maintain human health, to respond to tissue damage, and during the initiation of cancers and other human diseases. The laboratory has two general approaches. First, we investigate the molecular signaling pathways that commit an undifferentiated embryonic cell, the endoderm, to a particular cell type fate, using the specification of liver and pancreas cells as a model. In the past year, we developed a fate map of the foregut endoderm in the mouse embryo, we discovered how a gene regulatory protein controls morphogenesis so that endoderm cells are properly positioned to receive organ-inductive signals, and we found distinct roles for blood vessel cells in promoting the growth of liver and pancreatic tissues at the earliest stages of organ development. The second approach of the laboratory is to investigate ways that gene regulatory proteins control the packaging of DNA in the cell nucleus, to control gene activity. Biochemical studies revealed that the regulatory protein FoxA possesses a protein segment that interacts with chromosome structural proteins, or histones, and is necessary for exposing genes sequences in chromosomes that are otherwise hidden by the histone proteins. Understanding how regulatory proteins and cell signals control gene activity and cell type decisions in development will help guide future efforts to control the differentiation and function of cells at will.

 

Zhaolan (Joe) Zhou, Ph.D.

Epigenetic control of genome function in brain development and disease

Assistant Professor of Genetics
452A Clinical Research Building
Tel: 215-746-5025 / Fax: 215-573-7760
Email: zhaolan@mail.med.upenn.edu
Zhou lab

A fundamental question in biomedical research is how the brain executes genetic programs while maintaining the ability to adapt to the environment. The underlying molecular mechanisms are not well understood, but epigenetic regulation, mediated by DNA methylation and chromatin organization, provides an intricate platform bridging
genetics and the environment, and allows for the integration of intrinsic and environmental signals into the genome and subsequent translation of the genome into stable yet adaptive functions in the brain. While we can now profile genome-wide DNA methylation at single-base resolution, how the methylome is established and maintained,
and how the cells interpret the methylome to affect gene expression and chromatin structure remain poorly understood. Moreover, recent studies have challenged the stability of the methylome in postmitotic neurons and have coupled changes in DNA methylation at specific loci to adaptive behaviors. We are interested in understanding
how DNA methylation is coded and decoded genome-wide but with locus-specificity in neurons. Given the high abundance of hydroxymethylcytosine in the brain, we are also interested in understanding the role of the methylome in establishing and maintaining neuronal identity and the molecular mechanisms by which the methylome modulates genome function in the brain.