Education
- College:
Microbiology
University of Wyoming
Laramie, Wyoming
1982
- Graduate School:
Microbiology and Biochemistry
University of Wyoming
Laramie, Wyoming
1984
- Doctorate:
Molecular Genetics
Albert Einstein College of Medicine
Bronx, New York
1989
- Postdoctoral Fellow
Stanford University School of Medicine
Departments of Developmental Biology, Genetics and HHMI
Stanford, California
Positions and Honors
- Associate Professor
Oncology Institute and Department of Pathology
Cardinal Bernardin Cancer Center
Loyola University of Chicago
Stritch School of Medicine
Maywood, IL
2004-present
- Assistant Professor
Departments of Biology and Chemistry
Program in Biochemistry
Syracuse University
1997-2003
- Assistant Professor (Adjunct)
Department of Biochemistry and Molecular Biology
SUNY Upstate Medical University
Syracuse, NY
1997-2003
- Helen Hay Whitney Postdoctoral Fellow
HHMI Research Fellow with Dr. Matthew P. Scott
HHMI and Departments of Developmental Biology and Genetics
Stanford Univ. School of Medicine
Stanford, CA
1991-1996
- Postdoctoral Research Scholar
with Dr. L. Shapiro
Department of Developmental Biology
Stanford Univ. School of Medicine
Stanford, CA
1989-1991
- Graduate Student
with Dr. L. Shapiro
Department of Molecular Genetics
Albert Einstein College of Medicine, Bronx, New York and Department of Microbiology
Columbia University
College of Physicians and Surgeons
New York, New York
1985-1989
- Graduate student
with Dr. P. Bear
Department of Microbiology and Biochemistry
University of Wyoming
1982-1984
Research Overview
In most living cells, chromosomes are formed from highly condensed DNA and basic proteins that function to compact the chromosomes into a structure called chromatin. Our research is focused on understanding the multitude of critically important roles chromatin structure plays in normal development and disease. In particular, we study a highly conserved group of proteins that form a complex whose main function is to regulate gene expression through direct effects on chromatin structure. When components of this complex are missing or mutated, cells lose the ability to properly control their fates and growth, leading to a variety of diseases including aggressive cancers.
Research Description
A fundamental challenge among all multicellular eucaryotes is coordinating the expression of critically important genes in different cells throughout development to produce a fully functional adult. This coordination is accomplished by short-range inductive signals between cells that rely on diffusible peptides and/or direct cell contacts to initiate intracellular signaling cascades that ultimately influence the expression of specific target genes. Chromatin has emerged as one of the primary obstacles with which the cell’s transcription and replication machinery must contend. Factors necessary to transcribe or replicate DNA must gain access to regulatory sites that are packaged into nucleosomes and higher order structures. This is especially problematic when cells are in mitosis and chromatin is extremely condensed. Energy dependent chromatin remodeling complexes have evolved to locally decondense regions to assist in factor binding. The best studied of these complexes is the highly conserved SWI/SNF complex, found in yeast, flies and mammals, that is required for the activation of many, but not all genes. These complexes are very large (~2-MDa) and are composed of 8-11 polypeptides. Recent work with the purified yeast and mammalian complexes has elucidated many of the biochemical properties involved in chromatin remodeling; though many aspects regarding the in vivo biological functions are unclear. For example, while only one subunit has any identified catalytic activity, the remaining subunits are necessary for full in vivo function, modulating the complex activities or targeting it to specific genes or processes. Significant questions remain, such as why so many subunits and how do they individually contribute to the functions of the complex? Do any of the subunits have roles independent of the complex? Also, the complex appears to influence gene regulation both positively and negatively (activation and repression). How is this accomplished and is the regulation direct or indirect? What are the in vivo targets of the complex and how are they selected? Drosophila offers an ideal system for examining these questions, with the full array of genetic, biochemical and cell biological tools available, including a completed genome sequence and a wealth of existing mutations. Drosophila research also provides a detailed developmental framework to bridge these disciplines.
Our projects utilize molecular, genetic and biochemical analysis of the Drosophila SWI/SNF complex, known as the Brahma (BRM) complex to address these questions. The efforts are focused on one of the most highly conserved and critically important components, known as SNR1. This subunit is crucial in both flies and humans for coordinating or targeting specific protein interactions between the complex and a variety of transcription factors and cell cycle regulatory proteins. We isolated a temperature sensitive snr1 mutant that allows for conditional removal of snr1 function, allowing us to fully characterize the biological requirements for SNR1 during development. This is especially important as the snr1 gene is essential in flies and loss of its human counterpart INI1 has been directly linked with aggressive childhood cancers and T-cell lymphomas. Thus, SNR1/INI1defines a new class of extremely potent tumor suppressors that function to regulate chromatin accessibility. We use a combination of genetic and biochemical studies, including DNA microarray analyses and chromatin immunoprecipitation to gain a much needed view of the range of targets of the complex in higher eucaryotes, setting the stage for a full investigation of how those targets are selected and regulated in developing tissues. The broader scientific impacts of our studies are that we can gain critically needed insight into the functional relationships among subunits of a large and extremely important chromatin remodeling complex, better understand the biological significance of chromatin remodeling in normal developmental processes including control of cell growth and reveal how loss of SNR1/INI1 leads to the unanticipated rapid onset of metastatic cancers.
Publications
View a partial list of
Dr. Dingwall's publications through the National Library of
Medicine's PubMed online database. |
