Richard N. FreimanAssociate Professor of Medical Science
Richard Freiman is molecular geneticist studying fundamental mechanisms of transcriptional regulation in mammalian development and human disease. Before joining the Brown faculty in 2003, Dr. Freiman completed graduate training in mechanisms garnering eukaryotic transcriptional regulation. He received his Ph.D. in Genetics from SUNY Stony Brook in 1997. His thesis research, conducted at Cold Spring Harbor Laboratory, involved elucidation of critical host cell-viral interactions regulating viral and cellular gene expression programs. In 1998, he moved to UC Berkeley where he conducted postdoctoral studies on mechanisms of tissue-specific gene expression. This work led to the discovery that components of general transcription factor complexes play direct and selective roles in mammalian development. He continues this research at Brown, using gene targeting in the mouse as the primary tool to characterize transcriptional regulators in mammalian reproduction and development. His recent work focuses on understanding the molecular etiology of infertility and ovarian cancer in women and mechanisms of spermatogonial stem cell regulation in men. He teaches courses on cell and molecular biology and stem cells.
Lovasco LA, Seymour, KA, Zafra K, O’Brien, CW, Schorl, C and RN Freiman. (2010). Accelerated ovarian aging in the absence of the transcription regulator TAF4B in mice. Biol. Reprod. 82: 23-34. PMID: 19684329.
Freiman, R.N. Specific variants of general transcription factors regulate germ cell development in diverse organisms. BBA-Gene Regulatory Mechanisms 1789: 161-6 (2009).
Gyuris, A., Donovan, D.J., Seymour, K.A., Lovasco, L.A., Smilowitz, N., Halperin, A., Klysik, J. and Freiman, R.N. The Chromatin Targeting Protein Brd2 is Required for Neural Tube Closure and Embryogenesis. BBA-Gene Regulatory Mechanisms 1789: 413-21 (2009).
Voronina, E., Lovasco, L.A., Gyuris, A., Baumgartner, R.A., Parlow, A.F. and Freiman, R.N. Ovarian Granulosa Cell Survival and Proliferation Requires the Gonad-Selective TFIID Subunit TAF4b. Dev. Biol. 303: 715-26 (2007).
Geles, KG, Freiman, RN, Liu W-L, Zheng, S, Voronina, E and Tjian R. (2006). Cell type-selective induction of c-jun by TAF4b directs ovarian-specific transcription networks. PNAS: Feb.10.
Falender, AE, Freiman, RN, Geles, KG, Hwang, KS, Morris, PL, Tjian, R and Richards J.S. Maintenance of spermatogenesis requires TAF4b, a gonad specific component of TFIID. (2005) Genes & Dev. 19: 794-803.
Wessel, GM and Freiman, RN. (2005). Every Sperm - and Germ Cell Protocol - is Sacred. Development: 132: 5127-5128.
Freiman, R.N and Tjian, R. (2003). Regulating the regulators: Lysine modifications make their mark. Cell 112: 11-17
Freiman, R.N and Tjian, R. (2002). A glutamine-rich trail leads to transcription factors. Science 296: 2149-2150 .
Freiman, R.N., Albright, S.R., Chu, L.E., Zheng, S., Liang, H.-E., Sha, W.C. and Tjian, R. (2002). Redundant role of tissue-selective TAF II 105 in B lymphocytes. Mol. Cell. Biol. 22: 6564-6572 .
Freiman, R.N., Albright, S.R., Zheng, S., Sha, W.C., Hammer, R.E. and Tjian, R. (2001). Requirement of tissue-selective TBP-associated factor TAF II 105 in ovarian development. Science 293:2084-2087.
Our laboratory is interested in deciphering mechanisms of gene expression patterns critical for proper organ development and function in mammals. We primarily use gene targeting in the mouse as a genetic tool to perturb the normal function of gene regulatory proteins in mammalian development. As an application of our research, we aim to understand how the disruption of normal gene expression networks may affect the etiology of disease states in humans, such as infertility and ovarian cancer.
Transcriptional regulation is achieved by the coordinated interplay of numerous protein factors with regulatory control sequences coded in the genome. At present, many of the major components of the machinery regulating transcription in eukaryotes are well known. However, mechanisms by which this complex machinery achieves precise control of cell and tissue-specific programs of gene expression observed in multi-cellular organisms is poorly understood. Our laboratory is interested in deciphering mechanisms of gene expression patterns critical for proper organ development and function in mammals. Using the mouse as a rich genetic and developmental system, we plan to probe the biological function of various components of the transcriptional apparatus to uncover novel pathways of cell type specification. In addition to characterizing basic mechanisms of differentiation and development, we will utilize developmental defects in the mouse to model human disease states as potential avenues of therapeutic intervention. Research in the laboratory will focus on two related areas--roles of a specialized TFIID complex in reproduction and development and in the etiology of human disease states. The multi-protein complex TFIID is a general transcription factor at the core of the RNA polymerase II machinery. TFIID is composed of the TATA-binding protein (TBP) and several TBP-associated factors (TAFs). To test the hypothesis that TFIID functions in regulating tissue-specific programs of gene expression, we have characterized the biological role of a gonadal-enriched subunit of TFIID called TAF4b (formerly called TAFII105). Strikingly, female mice lacking TAF4b are infertile due to developmental defects in the ovary that prohibits proper oocyte growth and development. In addition, male TAF4b-deficient mice can undergo normal spermatogenic differentiation but fail to maintain spermatogenesis in adulthood. Based on these initial findings, we plan to characterize the normal expression patterns and functions of TAF4b in reproduction and gonadal development. Furthermore, we will characterize underlying molecular mechanisms controlling gonadal gene expression networks in the mouse. In combination with elucidating the normal developmental functions and mechanisms of TAF4b in reproduction, we will probe the function of TAF4b in humans as a potential cause of premature reproductive failure or infertility. Our recent work has unveiled an important function of TAF4b in the control of cellular proliferation in the ovary, and we will extend these studies to identify the potential deregulation of TAF4b-dependent processes in the context of ovarian cancer.
In addition to using the TAF4b-deficient mice as an inroad to studying reproductive development and disease, our laboratory will study functional roles of the chromatin modifying and remodeling machinery in mouse development and human disease. Histone modifications known to be important for the control of gene expression are phosphorylation, acetylation, and methylation. In addition, ATP-dependent chromatin remodeling complexes are critical for executing regulated gene- and tissue-specific programs of gene expression. Using the mouse as a model system, we will identify and characterize the function of selective components of the cellular machinery that modify and remodel chromatin in a tissue-specific manner. Such tissue-specific modifiers of chromatin will be targeted for disruption in the mouse and associated phenotypes, and gene expression pathways will be dissected. These studies are aimed at understanding basic mechanisms of tissue-specific gene expression pathways as well as how such pathways go awry in human diseases.
New Scholar Award in Aging (PI: Freiman, R.N.) 7/1/2006-06/30/2010
The Ellison Medical Foundation Direct Costs: $184,000
Germline Stem Cell Maintenance During Mammalian Spermatogenesis
The major goals of this project are to identify the potential functions of TAF4b in the regulation of testicular homeostasis and premature testicular aging in the context of the TAF4b-deficient mice.
Research Scholar Grant DMC-117629 (PI: Freiman, R.N.) 07/01/2009-06/30/2013
American Cancer Society Direct Costs: $720,000
TAF4b function in granulosa cell proliferation and ovarian tumorigenesis
The major goal of this project is to uncover the potential impact of TAF4b regulation in ovarian cancer using multiple mouse transgenic models.
1RO1 HD065445-01A2 (PI: Freiman, R.N.) 04/01/10-03/31/15
National Institutes of Health Direct Costs: $1,062,500
Ovarian-specific transcription networks regulated by the TFIID subunit TAF4b
The major goal of this project is to elucidate the mechanisms of the TAF4b subunit of TFIID in the regulation of ovarian-specific networks of gene expression.