Charles H.


"A Dr. Charles H. Best Postdoctoral Fellowship will be awarded to a highly qualified graduate (2 years or less postgraduate) in the field of molecular, genetic and genomic research. Applications should be addressed to one or two primary faculty members in the Donnelly Center for Cellular and Biomolecular Research (Andrews, Bader, Blencowe, Boone, Caudy, Emili, Fraser, Greenblatt, Hughes, Kim, Krause, Moffat, Morris, Roth, Ryu, Sidhu, Taipale, Zhang), whose interests match their own. Individual research programs include studies on gene regulation, signal transduction, development, systems biology, proteomics, computational biology and functional genomics and are carried out in the state-of-the-art Donnelly Centre . Upon agreement of sponsorship, the applicant must send a curriculum vitae, one page statement of research interests, transcripts, and three letters of reference to their sponsoring faculty mentor. The deadline for applications is late September annually. The successful applicant will be supported for up to two years with a generous stipend.

Descriptions of Recent Projects

Jingwen Song, PhD, McGill University

First observed in 1970 by electron microscopy, gene transcription is the process by which a DNA sequence is copied to make an RNA molecule, which then directs synthesis of the corresponding protein. Transcription consists of three stages: initiation, elongation and termination, which are carried out by a complex called RNA polymerase II (RNA Pol II). In transcription RNA molecules are synthesized as a linear readout of DNA until RNA Pol II encounters signals that tell it to stop, or terminate transcription; at this point the newly synthesized RNA is released from the DNA template. In human cells, transcription termination is a tightly controlled by protein factors associated with RNA Pol II.

Recent advances in cancer biology have revealed that dysregulation of transcription termination can be linked to cancer progression in both mouse and human cells. Abnormal expression of specific termination factors contributes to tumorigenesis. Dr. Jack Greenblatt's group has identified two Pol II-associated factors (RPRD1A and RPRD1B) that likely play a role in transcription termination. RPRD1B is found to be an oncoprotein which is over-expressed in some human cancers. However, the detailed mechanism of how RPRD proteins affect transcription termination in tumorigenesis remains unknown.

My current project is to determine the role of the RPRD proteins in termination of transcription. Working in the laboratory of Dr. Greenblatt, I am developing high-throughput RNA sequencing and gene-knockout screens to study how the RPRD proteins are involved in the regulation of transcription termination, by using both molecular and computational methods. I will also screen for compounds that might affect the termination process and consequently may inhibit cancer cell growth. This study will contribute to the current understanding of the regulatory roles of Pol II-associated proteins, and may have implications and clinical significance for future cancer therapy.

Eugenio Gallo, PhD, Carnegie-Mellon University

Scientific research in the 21st century will deliver tools against medical disorders that previously were impossible or unlikely to treat. One such disease is cancer (which is actually a large group of diseases characterized by abnormal cell growth); statistically one in three people in North America currently are likely to suffer from one or another form of cancer. The direct consequence of unregulated cell growth is the development of tumours that form a mass with the potential to invade or spread to other parts of the body, resulting in death. Tumour masses form unique micro-environments that recruit other non-cancerous cells and blood vasculature, which drive their nutrition, growth, and immune evasion.

Recent advances in cancer biology reveal that a particular family of proteins called integrins are associated with the development and progression of tumours. Integrin proteins are situated in the cell envelope and act as receptors that play a role in interactions with other cells and with the extracellular environment, where they play a pivotal role in cellular behaviour. Integrins regulate cellular activity in two ways. First they mediate the migration of cells by recognizing and attaching to another group of molecules called scaffolds. Second, they act as receptors to regulate signals inside the cell, which influence gene expression and subsequent regulation of cell survival, differentiation and proliferation.

My current research focuses on the study of integrin biology using the latest methods in genetics, and structural, molecular and cellular biology. The main emphasis is to understand the function and roles of different integrins in tumour biology. The second aim, is to develop therapeutic tools and reagents to target specific integrins with the aim of inhibiting tumour growth. Overall, the project offers the potential for the following: the identification and characterization of specific integrins associated with cancer, the development of new antibody tools to study cancer biology, and the generation of biological therapeutics to mitigate tumour development.

Marjan Barazandeh, PhD

All cells in an individual's body carry the same copy of the genome (the complete set of DNA). However, differences in the readout of genes and other DNA regions among various cell types are determined by the roles of proteins called regulatory transcription factors (TFs). TFs respond to intracellular or extracellular metabolic signals and control the expression of genes by binding to DNA and turning them on or off. TFs are important in regulating the read out of genes during early developmental of an organism. Their mis-function also play important roles in diseases, including cancer. Studying variation in the structure and role of TFs in individuals and across species helps us to understand natural process such as molecular evolution, as well as the pathologies of diseases.

TFs are usually highly conserved proteins, i.e. their amino acid sequence remains unchanged between species; they often perform similar functions in a wide variety of species as different as humans, worms, and flies. On the other hand, some classes of TF proteins are changing very rapidly through evolution. One of the most important of these classes is called Cys2His2 Zinc-Finger proteins (C2H2 ZFs); these have evolved rapidly in many mammalian species, resulting in new forms of this class of TFs. The selective forces of this rapid evolution are mainly unknown, as is the function of most of the hundreds of C2H2 ZF, even in humans. However, intriguing new findings suggest that a vertebrate-specific sub-family of C2H2 ZFs has evolved in such a way as to bind and control the expression of many newly-discovered DNA regions that do not code for proteins. The functions of these regions is largely unknown. They evolve rapidly, make up almost one-half of the human genome, and are probably implicated in genetic disorders and diseases in humans.

To determine the function of these DNA regions and their association with C2H2 ZFs, I propose to study the evolutionary patterns of both the C2H2 ZFs and their related DNA regions among different species. Therefore, in my postdoctoral project in Dr. Timothy Hughes's research group, I will use several molecular and computational methods to examine how these C2H2 ZFs and their related DNA regions have co-evolved in human and other vertebrates. The resulting findings will increase our current understanding of the regulatory functions of C2H2 ZFs and the DNA regions that they regulate, and potentially will lead to diagnosis and treatment options for the diseases influenced by these DNA regions.







Past Fellowship Holders

Marjan Barazandeh
BSc Shahid Beheshti Shahid Beheshti University (Tehran), MSc Tarbiat Modares University (Tehran), PhD University of Alberta

Tim Sterne-Weiler
BS University of California, Santa Cruz, MS University of California, Santa Cruz, PhD University of California, Santa Cruz

Jelena Tomic
PDF - The Donnelly Centre, University of Toronto, ON

Hamed Shateri Najafabadi
Postdoctoral Fellow, University of Toronto

Anna Lee
Bioinformatician - Ontario Institute for Cancer Research, Toronto ON

Jonathan Ellis
Research Associate - The Donnelly Centre, University of Toronto, ON

Lucia Caceres
Research Associate, Dalhousie University

Dewald van Dyk
Research Associate, University of Toronto

Mathieu Gabut
University of Lyon, France

Joseph Barash
Assistant Professor University of Pennsylvania

Franco Vizeacoumar
Research Associate - Donnelly Centre

Gwenael Badis-Breard
Staff Scientist, Institut Pasteur, France

Gordon Chua
Assistant Professor - University of Calgary

Xianchun Li
Assistant Professor - University of Arizona

Christine Misquitta
Senior Research Associate-Donnelly Centre

Armaity Davierwala
Consultant, Persistent Systems Ltd, India

Gareth Butland
Staff Scientist, Lawrence Berkeley Laboratories USA

Mark Lambermon
Senior QC Analyst, Active BioMaterials, Chicago, IL

Peixiang Wang
Staff Scientist, UHN, Toronto

Ping Yang
Genetic Counselor, Elizabeth Bruyere Centre, Ottawa