Molecular Genetics

 

Yosef Shaul, Head
The Oscar and Emma Getz Professorial Chair

The Department of Molecular Genetics investigates the molecular and genetic mechanisms of basic biological processes, in the context of both complex organism,such as human, mouse and Drosophila, and at the level of single cell organism and culture. A wide range of biological questions and hypotheses are addressed in the fields of development, cell biology, and human/mouse genetics, on the structure, expression, stability and function of proteins and on gene expression. Additionally, the fields of bioinformatics and computational biology, which are active in the department, provide powerful genome-wide approaches to modeling biological processes and their evolution.

A number of groups study the Drosophila model system from different aspects. The lab of Benny Shilo continued to focus on EGF receptor signaling in Drosophila. An intricate machinery for processing the activating ligands was uncovered. Interestingly, the amount of ligand that is secreted can be regulated by altering the intracellular compartment in which processing takes place. Once the ligand is secreted, distinct threshold responses are established. In a combination of experimental and computational work, a novel mechanism for creating such response thresholds was identified. In a different research avenue, novel insights into the mechanism of cell fusion during muscle development, and the involvement of the microfilament system in the process were uncovered. Talila Volk's lab focuses on mechanisms controlling tissue formation and organogenesis in developing Drosophila. They found that a splicing-dependent mechanism, controlled by the RNA-binding protein HOW, is a critical step in the induction of terminal differentiation of tendon and glial cells. HOW is essential for mesoderm invagination and spreading and the relevant target mRNAs were identified. In addition, they found that the extra cellular matrix protein Thrombospondin is essential for the specific adhesion of muscles with their corresponding tendon cell, a process that is regulated by a secreted growth factor DEgfl7. In addition they have identified a membrane protein that binds to the guiding receptor Roundabout to counteract its interaction with its ligand Slit. Studies are also conducted to characterize mechanisms involved in the formation of the Drosophila Blood Brain Barrier. Eli Arama’s laboratory is primarily concerned with the molecular, cellular, and anatomical mechanisms that underlie caspase activation in Drosophila. Previously they showed that spermatids normally eliminate the majority of their cytoplasm and organelles in an apoptosis-like process that requires canonical cell death proteins, including caspases. These observations, as well as recent studies by other groups counter the dogma that cells expressing active caspases are doomed to die. Currently, a major effort in his lab is being focused on the signaling pathways and molecular mechanisms that regulate caspase activation during cellular remodeling of the sperm and investigate how caspases facilitate cell terminal differentiation.

Mouse model systems are being approached for studying embryonic development and genetic diseases. Elazar Zelzer studies genetic and epigenetic mechanisms that regulate bone development. Their previous finding that VEGF is required for angiogenesis into developing bones, initiated their interest in this gene. By analyzing the effect of loss of VEGF function in different tissues involved in bone development, they have identified several unpredicted novel roles of VEGF during bone development. First, VEGF regulates early chondrogenesis during limb bud development. It also regulates chondrocytes survival. Finally, it stimulates bone formation by increasing the activity of osteoblasts, both in intramembranous and endochondral bones. By studying the expression patterns of VEGF they have identified a dynamic expression in skeletal tissues, consistent with its roles during several steps of bone development. Thus, the VEGF study has become a portal to greater understanding of skeletal development. Developmental aspects in the mammalian brain are being studied by Orly Reiner’s lab. One typical feature of the mammalian brain is that neurons are born in a region which is different from their final position. Their group is researching normal and abnormal processes of neuronal migration using a combination of mouse genetics, in utero electroporation, biochemistry, and cell biology methods. In particular they are involved in dissecting the role of lissencephaly-associated gene products (LIS1 and doublecortin, DCX). Their research has indicated to their importance in mediating signaling pathways, and regulating the microtubule and actin cytoskeleton during neuronal migration. Yoram Groner research focuses on disease conditions in which genetic predisposition of individual chromosome 21 genes play role. That is, how an extra copy of otherwise normal genes produces pathophysiological conditions in humans particularly in patients with Down syndrome. Gene-Knockout mice of individual genes are used to investigate the consequences of functional inactivation of candidate genes. Currently much of the studies focused on the biology of the transcription factors Runx1 and Runx3 that are master regulators of linage specific gene expression in developmental pathways using genetically modified cells and mouse models. Eran Eornstein team studies the roles of microRNAs (miRNA) in development, focusing on miRNA function in vertebrate organogenesis. miRNAs repress the expression of protein-coding mRNAs (targets), providing a previously unappreciated regulatory mechanism for gene expression. Upon binding of an individual miRNA, or a combination of several miRNAs to the 3' untranslated region of a target mRNA, either translation repression or mRNA cleavage is induced. They study the role of miRNA role in skull bone formation, in pancreas and beta-cell biology, in posttranscriptional regulation gene expression and in stochastic fate determination. These studies would reveal facets of miRNA biology and roles played by non coding RNAs in developmental biology and in evolution.

Basic cellular processes are being approached from the molecular angle, both in mammalian cells and in yeasts by several groups. The lab of Jeff Gerst focuses on how cells establish and maintain polarity in order for directed growth and cell division to occur. They are using the yeast, Saccharomyces cerevisiae, as a model system and have three major projects. The first examines the role of signaling pathways in the control of exocytosis at the level of membrane fusion and studies the role of kinases and phosphatases in regulation of the exocytic apparatus. The second focuses on the role of SNARE-binding proteins in endosomal protein sorting and the onset of human diseases involving defects in lysosomal storage. The third examines the role of mRNA trafficking in the regulation of basic cellular processes. Maya Schuldiner lab is interested in understanding the networks of proteins functioning together to create an optimal functioning ER. Since close to 30% of ER proteins have unknown functions, an important goal of the lab is to uncover biological roles for these proteins drawing from the systematic data collected in yeast and using different genetic and biochemical tools. They also use high throughput microscopic screening platforms to ask basic questions about ER structure and function such as trying to understand the molecular mechanisms of ER inheritance or the dynamics of protein movements in and out of this large and complex organelle. Adi Kimchi’s group studies programmed cell death, by proceeding from single gene studies towards global network analysis. By studying DAP-kinase and its close family homologs, DRP-1 and ZIP-kinase, new mechanisms which control the less characterized modules of cell death including autophagy and programmed necrosis have been discovered. Studies on DAP5 protein highlighted the role of cap-independent translation under stress and relaxed conditions, and initial research on DAP1 revealed the existence of a new scaffold protein, which is a suppressor of autophagy. The project on the global cell death network is based on a combinatorial knock down approach, which measures the outcome of epistatic interactions between the network’s proteins (around 150). By running this new methodology they proved that compensatory switches between functional modules contribute to the network’s robustness, and that inter-modular connectivity occurs at multiple positions via positive or negative interactions. The lab of Ari Elson studies the roles of protein tyrosine phosphatases (PTPs) in regulating physiological processes. Their goals are to uncover detailed molecular-level mechanisms, by which specific phosphatases affect discrete physiological outcomes by dephosphorylating specific substrates. Their current studies focus on PTPs Epsilon and Alpha; they are using molecular, cellular, and whole-animal systems to uncover the role of these phosphatases in regulating malignant transformation, bone metabolism, and regulation of body mass/obesity. Chaim Kahana’s group investigates polyamines in regulating cellular proliferation. AzI, is a homolog of ODC, but unlike ODC has no enzymatic activity and undergoes ubiquitin dependent degradation. His group also studies the growth advantage this protein provides to cells. These two aspects are investigated in relation to the interaction ability of AzI with three types of a polyamine induced protein termed antizyme (Az) that act as negative regulators of ODC. Another aspect of investigation concernes the possible involvement of 20S proteasomes in mediating ubiquitin independent cellular degradation. Finally, the lab investigates the role polyamines exert in regulating cellular functions with emphasis on regulating cellular proliferation. The team of Yosef Shaul studies the basic cellular processes of transcription, protein stability and DNA-damage signaling. These processes are investigated also with respect to understanding the molecular basis of cancer and virus-host cell interactions, using the hepatitis B virus (HBV) as a model. They discovered the pathway of “degradation by default” of proteins that are segmentally or fully intrinsically unstructured (IUPs or IDPs). This pathway is executed by the 20S proteasomes both in vitro and in vivo. They found NQO1, an NADH regulated enzyme to play a role of 20S proteasome gatekeeper to block degradation by default. Also they identified a new signaling axis whereby c-Abl, p73 and Yap respond to DNA damage insults to induce apoptosis or DNA repair. This signaling axis is in a crosstalk with the Hippo signaling that determines organs size.

Cytokine signaling is an additional studied theme. The lab of Leo Sachs continues their work on the cytokine mediated control of multiplication, differentiation and apoptosis of hematopoietic stem cells. In a recent study they showed that human cancers overexpress genes that are specific to a variety of normal human tissues. Michel Revel's group investigates regenerative medicine approaches to the treatment of diseases which destroy the myelin sheaths around nerves, such as various neuropathies, Multiple Sclerosis and spinal cord injuries. Efficient differentiation of mouse and human embryonic stem (ES) cells into oligodendrocyte precursors (OPC) was achieved and used to treat the brain of shiverer mutant mice suffering from dysmyelination. The group develops large scale culturing technology of human ES cells for cell therapy in clinical settings. They have obtained pancreatic islet cells that could be applied for the treatment of insulin-dependent diabetes. The lab of Menachem Rubinstein studies the role of several transcription factors in growth, differentiation, cell death and immune responses. They identified a heterodimeric complex of the transcription factors C/EBP-ß and IRF-1 as a mediator of interferon-gamma immunomodulatory activities. Currently, the group studies the various functions of the C/EBP family of transcription factors. In particular, the role of C/EBP-ß in tumor cell survival and pre-adipocyte differentiation. The group also studies the role of another family member – CHOP-10 in adipocyte cell death. Another research topic deals with regulation of IFN-a gene expression, trying to resolve the enigma of multi-gene family whose products have a practically identical function. Also, they continue the attempts to identify receptors of bereaved cytokines (the counterparts of orphan receptors).

A bioinformatics computational approach is being taken by a number of groups. In the lab of Doron Lancet, whole-genome analyses and comparative genomics are used to decipher the evolution of olfactory receptors, the largest gene superfamily in the human genome. Genetic variation is studied as a tool for understanding multigenic diseases such as schizophrenia, as well as personal variations in the sense of smell. This is aided by advanced instrumentation for detecting single nucleotide polymorphisms (SNPs) by robotized mass spectrometry. The group also develops GeneCards, a worldwide used compendium of human genes, which allows one to better analyses human genome information. In the realm of Systems Biology, prebiotic molecular networks are studied as a means for understanding the emergence of life on earth. Such analyses are relevant both for solving the profound question of how life emerged, as well as to better understand present day life, e.g. synthetic lethality in cancer cells. Rotem Sorek’s lab utilizes the vast amount of genomic data available for bacteria in order to study functional and evolutionary aspects of microbial biology. Projects in the lab include computational discovery of genes that are toxic to bacteria. They discovered that these uncloneable gaps are caused by genes that are toxic to E. coli. A second field of research involves next generation (‘Solexa’) sequencing of microbial transcriptomes, in order to study RNA-based regulation in prokaryotes. They detect a large number of functional novel non-coding RNAs and cis-antisense transcripts that play key regulatory roles in the organisms they are found at. Next generation technologies are also used for whole-genome sequencing of bacteria. They sequenced 7 strains of Buchnera, a bacterial obligate symbiont of insects, and characterized its mode of genomic evolution across time. The lab of Shmuel Pietrokovski studies the relations between protein sequence, structure and function. He pursues this goal by computational and experimental approaches. Computationally he developed methods to compare conserved protein sequence motifs, and to analyze protein structures. Intein protein-splicing domains and related domains are studied. He is examining the evolution, biochemical activity and cellular function of these ancient domains that are involved in various post-translational modifications in animals and microbes.

Two groups take more system and computational biology approach. In the lab of Naama Barkai they aim at deducing design principles of biological networks. The two main research programs include bioinformatics studies of large-scale data and modeling of relatively isolated subsystems. They analyzed genome-wide transcription data between organisms, focusing on related yeast species. They classified inter-species differences in gene expression pattern. They identified a major re-wiring of the yeast transcription network, which is connected to the emergent of anaerobic growth capacity and characterized a connection between TATA-based regulation and evolvability of gene expression. The modeling studies focused on two systems: the spindle assembly checkpoint and gradient detection during yeast mating. In both systems they characterized biological constraints that the respective system need to overcome thus limiting the possible designs of the underlying biological networks. A central challenge for living organisms is to execute intricate cellular programs in the face of environmental variations, genetic changes and the inherent noise of molecular processes. Tzachi Pilpel group aims at understanding such programs by deciphering the structure, function and evolution of regulatory networks that control them. They study these networks at the level of their structure and at the level of their function in higher-level processes and phenomena. At the structure level we decipher networks controlling transcription, translation, mRNA degradation and non-coding RNAs. At the higher functional level we study how entire processes and phenomena such as genetic backup, stress response, and evolutionary divergence of species, are regulated through the various gene expression levels. In our research we combine theory, computations, and experimental work.

In summary, the department combines structural genomic approaches with functional "post-genomic" studies. Moreover, the employed multiple model organisms, namely yeast, fly, mouse and human, removes the species barrier and set the stage of viewing a single biological process from different angels, thus benefiting from the various genetic and molecular tools that each system offers.

http://www.weizmann.ac.il/molgen/

Research Staff, Visitors and Students

Professors

Naama Barkai, Ph.D., The Hebrew University of Jerusalem, Jerusalem, Israel
Jeffrey Gerst, Ph.D., Weizmann Institute of Science, Rehovot, Israel
       The Besen-Brender Professorial Chair of Microbiology and Parasitology
Yoram Groner, Ph.D., Weizmann Institute of Science, Rehovot, Israel (on extension of service)
       The Dr. Barnet Berris Professorial Chair of Cancer Research
Chaim Kahana, Ph.D., Weizmann Institute of Science, Rehovot, Israel
       The Jules J. Mallon Professorial Chair of Biochemistry
Adi Kimchi, Ph.D., Tel Aviv University, Tel-Aviv, Israel
       The Helena Rubinstein Professorial Chair in Cancer Research
Doron Lancet, Ph.D., Weizmann Institute of Science, Rehovot, Israel
       The Ralph D. and Lois R. Silver Professorial Chair of Human Genomics
Orly Reiner, Ph.D., Weizmann Institute of Science, Rehovot, Israel
       The Bernstein-Mason Professorial Chair of Neurochemistry
Menachem Rubinstein, Ph.D., Weizmann Institute of Science, Rehovot, Israel
       The Edna and Mickey Weiss Professorial Chair of Cytokines Research
Yosef Shaul, Ph.D., Weizmann Institute of Science, Rehovot, Israel
       The Oscar and Emma Getz Professorial Chair
Ben-Zion Shilo, Ph.D., The Hebrew University of Jerusalem, Jerusalem, Israel
       The Hilda and Cecil Lewis Professorial Chair of Molecular Genetics

Professors Emeriti

Michel Revel, Ph.D., University of Strasbourg, France
Leo Sachs, Ph.D., University of Cabmridge, Cambridge, United Kingdom
       The Otto Meyerhof Chair of Molecular Biology
Ernest Winocour, Ph.D., The Hebrew University of Jerusalem, Jerusalem, Israel

Associate Professors

Ari Elson, Ph.D., Weizmann Institute of Science, Rehovot, Israel
       The Marshall and Renette Ezralow Professorial Chair
Shmuel Pietrokovski, Ph.D., Weizmann Institute of Science, Rehovot, Israel
       The Hermann and Lilly Schilling Foundation Professorial Chair
Yitzhak Pilpel, Ph.D., Weizmann Institute of Science, Rehovot, Israel
Talila Volk, Ph.D., Weizmann Institute of Science, Rehovot, Israel
       The Professor Sir Ernest B. Chain Professorial Chair

Senior Research Fellow

Daniela Novick, Ph.D., Weizmann Institute of Science, Rehovot, Israel

Senior Scientists

Eli Arama, Ph.D., Technion - Israel Institute of Technology, Haifa, Israel
       Yigal Allon Fellow
       Incumbent of the Corinne S. Koshland Career Development Chair
Eran Hornstein, Ph.D., The Hebrew University of Jerusalem, Jerusalem, Israel
       Yigal Allon Fellow
       Incumbent of the Helen and Milton A. Kimmelman Career Development Chair
Maya Schuldiner, Ph.D., The Hebrew University of Jerusalem, Jerusalem, Israel
Rotem Sorek, Ph.D., Tel Aviv University, Tel-Aviv, Israel
       Yigal Allon Fellow
       Incumbent of the Rowland and Sylvia Schaefer Career Development Chair
Elazar Zelzer, Ph.D., Weizmann Institute of Science, Rehovot, Israel
       Incumbent of the Martha S. Sagon Career Development Chair

Senior Staff Scientists

Judith Chebath, Ph.D., University of Marseilles, France
Ditsa Levanon, Ph.D., Weizmann Institute of Science, Rehovot, Israel
Eyal Schejter, Ph.D., Weizmann Institute of Science, Rehovot, Israel

Associate Staff Scientists

Edna Ben-Asher, Ph.D., Weizmann Institute of Science, Rehovot, Israel
Tsviya Olender, Ph.D., Weizmann Institute of Science, Rehovot, Israel

Assistant Staff Scientists

Gil Amitai, Ph.D., Weizmann Institute of Science, Rehovot, Israel
Orna Dahan, Ph.D., Tel Aviv University, Tel-Aviv, Israel
Nina Reuven, Ph.D., Weizmann Institute of Science, Rehovot, Israel
Tamar Sapir, Ph.D., Weizmann Institute of Science, Rehovot, Israel

Senior Interns

Nurit Avraham Tayar, Ph.D., Weizmann Institute of Science, Rehovot, Israel
Sergey Bujanover, Ph.D., The Hebrew University of Jerusaelm, Jerusalem, Israel (left January 2010)
Yossi Kalifa, Ph.D., Ben-Gurion University of the Negev, Beer-Sheva, Israel
Dalia Rosin-Grunewald, Ph.D., Weizmann Institute of Science, Rehovot, Israel (left November 2010)
Gil Stelzer, Ph.D., Bar-Ilan University, Ramat-Gan, Israel

Interns

Galit Cohen, Ph.D., Weizmann Institute of Science, Rehovot, Israel
Ofir Meir, Ph.D., Weizmann Institute of Science, Rehovot, Israel

Engineer

Joseph Lotem, Ph.D., Weizmann Institute of Science, Rehovot, Israel

Consultants

Shani Brown
Avshalom Elitzur, Iyar the Israeli Institute for Advanced Research
Ofer Fainero, Hillel Yaffe Medical Center, Technion, Haifa, Israel
Rita Gelin Licht
Gabriel Gerlitz
Ruth Gross-Isseroff
Jacob (Yaqub) Hanna, Whitehead Institute for Biomedical Research, Cambridge, USA
Tsippi Iny Stein
Tal Julie Melkman-Zehavi (left November 2010)
Shay Rotkopf
Leo Sachs
Gil Stelzer (left April 2010)
Ernest Winocour

Visiting Scientists

Vasudheva Reddy Akepati, Free Univ., Berlin, Germany
Ziv Bar-Joseph, Carnegie Mellon University , Pittsburgh, PA, U.S.A.
Dana Barnea
Ivo Gomperts Boneca, Pasteur Institute, France
Neta Erez, UCSF, U.S.A.
Shai Fuchs, Schneider Hospital, Israel
Eugene Kolker, Seattle Children's Research Institute, U.S.A.
Natalio Krasnogor, University of Nottingham School of Computer Science, UK
Yuval Ltan
Donna Martin, University of Michigan, U.S.A.
Malcolm Arthur Mclean, University of Leeds, UK
Doron Rapaport, University of Tubingen, Germany
Gerald Scwank
Raphael Zidovetzki, University of California at Riverside, U.S.A.

Postdoctoral Fellows

Efrat Assa-Kunik, Ph.D., Weizmann Institute of Science, Israel
Nurit Avraham, Ph.D., Weizmann Institute of Science, Israel
Omri Bauer, Weizmann Institute of Science, Israel
Dorit Cohen, Weizmann Institute of Science, Israel
Judith Cohen, Ph.D., Weizmann Institute of Science, Israel
Mally Dori-Bachash, Agriculture Faculty, Israel
Avital Eisenberg-Lerner, Weizmann Institute of Science, Israel
Yael Elbaz, Hebrew University of Jerusalem, Israel
Idit Eshkar-Oren, Weizmann Institute of Science, Israel
Noga Gadir, Ph.D., The Graduate Center of The City University Of New
Tali Garin, Weizmann Institute of Science, Israel
Rita Gelin Licht, Weizmann Institute of Science, Israel
Eliezer Gilsohn, Weizmann Institute of Science, Israel
Yael Gruenbaum-Cohen, Hebrew University of Jerusalem, Israel
Liora Haim-Vilmovsky, Weizmann Institute of Science, Israel
Arye Harel, Ph.D.
Yehudit Hasin, Weizmann Institute of Science, Israel
Gil Hornung, Weizmann Institute of Science, Israel
Aron Inger, Ph.D., Weizmann Institute of Science, Israel
Vydehi Kanneganti, Ph.D., School of Biotech, Madurai Kamaraj University
Iris Karunker-Hazan, Agriculture Faculty, Israel
Sagi Levy, Weizmann Institute of Science, Israel
Idit Livnat, Weizmann Institute of Science, Israel
Ofir Meir, Weizmann Institute of Science, Israel
Amir Mitchell, Weizmann Institute of Science, Israel
Inbal Mor, Ph.D., Hebrew University of Jerusalem, Israel
Yaron Mosesson, Weizmann Institute of Science, Israel
Ronit Nir, Weizmann Institute of Science, Israel
Tal Noy-Porat, Tel-Aviv University, Israel
Galia Oberkovitz, Weizmann Institute of Science, Israel
Pravinkumar Purushothaman, Ph.D., School of Biotech, Madurai Kamaraj University
Shay Rotkopf, Ph.D., Institute of Molecular Pathology (Imp)
Vered Salomon, Hebrew University of Jerusalem, Israel
Yehuda Salzberg, Bar-Ilan University, Israel
Schraga Schwartz, Tel-Aviv University, Israel
Yishay Shoval, Weizmann Institute of Science, Israel
Boris Slobodin, Weizmann Institute of Science, Israel
Zohar Snapir, Weizmann Institute of Science, Israel
Adi Stern, Tel-Aviv University, Israel
Itay Tirosh, Weizmann Institute of Science, Israel
Keren Yacobi-Sharon, Ph.D., Weizmann Institute of Science, Israel
Liat Yakir-Tamang, Weizmann Institute of Science, Israel
Yael Yoffe, Ben-Gurion University, Israel
Shaul Yogev, Weizmann Institute of Science, Israel
Daniela Zalcenstein (Nee Ama), Ph.D., Weizmann Institute of Science, Israel

Research Students

Yaarit Adamovich Lior Aram
Omer Barad Omri Bauer
Oren Ben-Ami Dan Ben-Zvi
Yaara Ber Assaf Biran
Einat Blitz Zohar Bloom
Karen Rae Bone Merav Branski Arieli
Michal Breker Shirly Brenner
Elik Chapnik Yifat Cohen
Yosef Dicken Niv Dobzinski
Efrat Dvash Avital Eisenberg-Lerner
Anna Maria Emde Idit Eshkar-Oren
Eynat Finkelshtein Danit Finkelshtein - Beker
Anat Florentin Tali Garin
Erez Geron Noga Gershoni-Emek
Boaz Gildor Hila Gingold
Roni Golan-Lavi Anna Gorelik
Ben Gradus Liora Haim-Vilmovsky
Nofar Harpaz Yehudit Hasin-Brumshtein
Michal Haskel Ittah Anna Kaplan
Yosef Kaplan Rom Keshet
Ifat Keydar Itay Koren
Sharon Kredo Guy Landau
Asaf Levy Sagi Levy
Einat Levy-Apter Noa Liberman
Idit Livnat Mati Mann
Omer Markovitch Victoria Meltser
Karin Mittelman Ofer Moldavski
Sivan Navon Ronit Nir
Elly Ordan Niv Pencovich
Noa Rappaport Liat Ravid
Inna Ricardo-Lax Chagai Rot
Tal Rousso Liat Rousso Noori
Assaf D. Rubinstein Hila Sberro Livnat
Michal Segal Ophir Shalem
Matan Shanzer Adi Shiloah
Liron Shiran-Gal Yishay Shoval
Yulia Shwartz Boris Slobodin
Zohar Snapir Ilya Soifer
Tomer Stern Zvi Tamari
Hadas Tamir Peter Tsvetkov
Kfir Baruch Umansky Noam Vardi
Ilya Venger Bernardo Vidne
Omri Wurtzel Shaul Yogev
Avihu Yona


Administrator

Yuri Magidov