Research
Research Programs
Gene Regulation and Functional Genomics
Program Members | Research Highlights | Contacts
Cancer is fundamentally a disease of disordered gene expression. Abnormal gene expression in cancer cells may be due to mutations within genes or closely linked DNA that regulates activity of those genes, deletions that remove various genes and gene regulatory sequences, amplification of genomic regions containing various genes, fusions of two genes by recombination between DNA sequences, or epigenetic changes - non-mutational modifications of DNA or of DNA-binding proteins that alter gene expression in a manner that can be transmitted to progeny cells over the course of multiple cell divisions. Furthermore, gene expression in cancer cells can be affected by perturbations in the machinery responsible for production or activity of proteins, such as systems that control the synthesis, modification, or degradation of proteins. If the changes regulate expression of other genes, as is often the case, there can be a large series of secondary effects on gene expression. It is the aggregate result of all these changes - multiple primary changes in gene expression plus the secondary changes, and beyond - that render a cell fully malignant.
The members of the Gene Regulation and Functional Genomics Program study all aspects of gene alterations in cancer. These studies include the discovery of mutations in genes and DNA that cause cancer; analysis of genomic changes and their functional consequences on gene expression; characterization of mechanisms that control protein production from genes; epigenetics; protein structure; and the analysis of large scale genomic data. Some researchers focus on specific genes in individual types of cancers, whereas others are involved in analyzing large numbers of genes and their expression in cancers both at diagnosis and during progression of the disease. In practical terms, this research has implications for improved cancer diagnosis and prognostic assessment of tumors, therapeutic responsiveness of tumors, and pre-symptomatic screening for cancers, all through the discovery of changes in genes and their expression characteristic of those cancers. In addition, reversal or neutralization of the changes in gene expression offer attractive targets for the development of new anti-cancer drugs and therapeutic strategies.
Jeffrey Sklar, MD, PhD, Program Co-Director; Professor of Pathology and Laboratory Medicine; Director of Molecular Diagnostics Program, Department of Pathology
Sherman Weissman, MD, Program Co-Director; Sterling Professor of Genetics
Susan Baserga, MD, PhD, Professor of Molecular Biophysics and Biochemistry, Therapeutic Radiology and Genetics
Demetrios Braddock, MD, Ph., Assistant Professor of Pathology
Jose Costa, MD, Professor and Vice-Chairman of Pathology
Alan Garen, PhD, Professor of Molecular Biophysics and Biochemistry
Antonio Giraldez, PhD, Assistant Professor of Genetic
Ruth Halaban, PhD, Senior Research Scientist in Dermatology
Tae Hoon Kim, PhD, Assistant Professor of Genetics
William Konigsberg, PhD, Professor of Molecular Biophysics and
Biochemistry
Paul Lizardi, PhD, Professor of Pathology
John Sinard, M.D., PhD, Professor of Pathology and Ophthalmology and Visual Science
Frank Slack, PhD, Associate Professor of Molecular, Cellular and Developmental Biology
Michael Snyder, PhD, Edward B. Cullman Professor of Molecular,Cellular and Developmental Biology and of Molecular Biophysics and Biochemistry
Hugh Taylor, MD, Professor of Obstetrics, Gynecology and Reproductive Sciences; Associate Professor of Molecular, Cellular and Developmental Biology
David Tuck, MD, Assistant Professor of Pathology
Kenneth Williams, PhD, Professor (Adjunct) of Research in Molecular Biophysics and Biochemistry
- Discovery that microRNAs may regulate expression of certain cancer genes in tumors of the lung and other organs (Dr. Slack). These small RNA molecules may be useful as diagnostic markers or as targets for therapy in many different cancers.
- Development of methods to assess changes in the binding of proteins to DNA on a genome-wide basis and global analysis of structural variation within the genome (Drs. Snyder and Weissman). These methods and findings have elucidated the extent of variation in the genome and possible effects on cancer pre-disposition and progression.
- Development of new techniques to investigate methylation of DNA within the genome (Drs. Lizardi and Costa). Methylation of DNA can be useful diagnostically and as an indication of altered expression of specific genes in cancer. These investigators are currently focusing on cancers of the head and neck.
- Development of an experimental therapy for cancer, targeting tissue factor (thromboplastin) in newly formed blood vessels of tumors (Drs. Garen and Konigsberg).
- Discovery of DNA rearrangements in Polycomb group genes within endometrial tumors and the demonstration that such rearrangements mimic trans-splicing of RNAs in normal tissues (Dr. Sklar). This work suggests the mechanism by which gene fusions induce many different types of cancers, especially leukemias, lymphomas, and sarcomas.
Contacts
Jeffrey Sklar, MD, PhD, Program Co-Director
(203) 785-6828
jeffrey.sklar@yale.edu
Sherman Weissman, MD, Program Co-Director
(203) 737-2281
sherman.weissman@Yale.edu