Richard N Freiman
Richard N Freiman
Professor of Molecular Biology, Cell Biology and Biochemistry, Vice Chair of Molecular Biology, Cell Biology and Biochemistry, Professor of Obstetrics and Gynecology
Overview
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.
Brown Affiliations
Research Areas
Aging | developmental biology | gene expression | genetics | infertility | Notch | ovarian cancer | ovary | reproductive biology | stem cells | testis | transcription | transgenic mice
On the Web
Publications Visualize it
| "Transcription and chromatin regulation by TAF4b during cellular quiescence of developing prospermatogonia." 2023. |
| "A bioinformatic analysis of WFDC2 (HE4) expression in high grade serous ovarian cancer reveals tumor-specific changes in metabolic and extracellular matrix gene expression." 2022. |
| Gura MA, Relovská S, Abt KM, Seymour KA, Wu T, Kaya H, Turner JMA, Fazzio TG, Freiman RN. "TAF4b transcription networks regulating early oocyte differentiation." Development, vol. 149, no. 3, 2022. |
| Sloutskin, Anna, Shir-Shapira, Hila, Freiman, Richard N., Juven-Gershon, Tamar. "The Core Promoter Is a Regulatory Hub for Developmental Gene Expression." Frontiers in Cell and Developmental Biology, vol. 9, 2021. |
| Gura MA, Mikedis MM, Seymour KA, de Rooij DG, Page DC, Freiman RN. "Dynamic and regulated TAF gene expression during mouse embryonic germ cell development." PLOS Genetics, vol. 16, no. 1, 2020, pp. e1008515. |
| Gustafson, Eric A., Seymour, Kimberly A., Sigrist, Kirsten, Rooij, Dirk G. D. E., Freiman, Richard N. "ZFP628 Is a TAF4b-Interacting Transcription Factor Required for Mouse Spermiogenesis." Molecular and Cellular Biology, vol. 40, no. 7, 2020. |
| Grive KJ, Gustafson EA, Seymour KA, Baddoo M, Schorl C, Golnoski K, Rajkovic A, Brodsky AS, Freiman RN. "TAF4b Regulates Oocyte-Specific Genes Essential for Meiosis." PLOS Genetics, vol. 12, no. 6, 2016, pp. e1006128. |
| Brown, Caitlin W., Brodsky, Alexander S., Freiman, Richard N. "Abstract POSTER-BIOL-1352: Notch3 promotes anoikis resistance in ovarian cancer." Clin Cancer Res, vol. 21, no. 16 Supplement, 2015, pp. POSTER-BIOL-1352-POSTER-BIOL-1352. |
| Lovasco, Lindsay A., Gustafson, Eric A., Seymour, Kimberly A., de Rooij, Dirk G., Freiman, Richard N. "TAF4b is Required for Mouse Spermatogonial Stem Cell Development." STEM CELLS, vol. 33, no. 4, 2015, pp. 1267-1276. |
| Grive KJ, Freiman RN. "The developmental origins of the mammalian ovarian reserve." Development, vol. 142, no. 15, 2015, pp. 2554-63. |
| Brown, C. W., Brodsky, A. S., Freiman, R. N. "Notch3 Overexpression Promotes Anoikis Resistance in Epithelial Ovarian Cancer via Upregulation of COL4A2." Molecular Cancer Research, vol. 13, no. 1, 2014, pp. 78-85. |
| Grive KJ, Seymour KA, Mehta R, Freiman RN. "TAF4b promotes mouse primordial follicle assembly and oocyte survival." Developmental Biology, vol. 392, no. 1, 2014, pp. 42-51. |
| Grive, Kathryn Jennifer, Ribiero, Jennifer R., Seymour, Kimberly A., Freiman, Richard N. "TAF4b promotes oocyte survival and proper ovarian chromatin state in the mouse." RA, 2014. |
| Ribeiro JR, Lovasco LA, Vanderhyden BC, Freiman RN. "Targeting TBP-Associated Factors in Ovarian Cancer." Frontiers in Oncology, vol. 4, 2014, pp. 45. |
| Wardell, Jennifer R., Grive, Kathryn J., Hodgkinson, Kendra M., Binder, April K., Seymour, Kimberly A., Lovasco, Lindsay A., Korach, Ken S., Vanderhyden, Barbara C., Freiman, Richard N. "Abstract A81: Estrogen-responsiveness of the TFIID subunit TAF4B and its potential function in ovarian cancer, epigenetic regulation and meiotic DNA repair." Clin Cancer Res, vol. 19, no. 19 Supplement, 2013, pp. A81-A81. |
| Wardell JR, Hodgkinson KM, Binder AK, Seymour KA, Korach KS, Vanderhyden BC, Freiman RN. "Estrogen responsiveness of the TFIID subunit TAF4B in the normal mouse ovary and in ovarian tumors." Biology of Reproduction, vol. 89, no. 5, 2013, pp. 116. |
| Freiman RN. "Processing the complexities of transcription." Developmental Cell, vol. 27, no. 2, 2013, pp. 123-4. |
| Reich A, Neretti N, Freiman RN, Wessel GM. "Transcriptome variance in single oocytes within, and between, genotypes." Mol. Reprod. Dev., vol. 79, no. 8, 2012, pp. 502-3. |
| Lovasco LA, Seymour KA, Zafra K, O'Brien CW, Schorl C, Freiman RN. "Accelerated ovarian aging in the absence of the transcription regulator TAF4B in mice." Biology of Reproduction, vol. 82, no. 1, 2010, pp. 23-34. |
| Freiman RN. "Specific variants of general transcription factors regulate germ cell development in diverse organisms." Biochimica et biophysica acta, vol. 1789, no. 3, 2009, pp. 161-6. |
| Lovasco, Lindsay, Freiman, Richard. "The changing distribution of sperm MIWI." Mol. Reprod. Dev., vol. 76, no. 2, 2009, pp. 119-119. |
| Gyuris A, Donovan DJ, Seymour KA, Lovasco LA, Smilowitz NR, Halperin AL, Klysik JE, Freiman RN. "The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesis." Biochimica et biophysica acta, vol. 1789, no. 5, 2009, pp. 413-21. |
| Voronina E, Lovasco LA, Gyuris A, Baumgartner RA, Parlow AF, Freiman RN. "Ovarian granulosa cell survival and proliferation requires the gonad-selective TFIID subunit TAF4b." Developmental Biology, vol. 303, no. 2, 2007, pp. 715-26. |
| Geles KG, Freiman RN, Liu WL, Zheng S, Voronina E, Tjian R. "Cell-type-selective induction of c-jun by TAF4b directs ovarian-specific transcription networks." Proceedings of the National Academy of Sciences, vol. 103, no. 8, 2006, pp. 2594-9. |
| Falender AE, Freiman RN, Geles KG, Lo KC, Hwang K, Lamb DJ, Morris PL, Tjian R, Richards JS. "Maintenance of spermatogenesis requires TAF4b, a gonad-specific subunit of TFIID." Genes & Development, vol. 19, no. 7, 2005, pp. 794-803. |
| Freiman RN, Tjian R. "Regulating the regulators: lysine modifications make their mark." Cell, vol. 112, no. 1, 2003, pp. 11-7. |
| Freiman RN, Tjian R. "Neurodegeneration. A glutamine-rich trail leads to transcription factors." Science, vol. 296, no. 5576, 2002, pp. 2149-50. |
| Freiman RN, Albright SR, Chu LE, Zheng S, Liang HE, Sha WC, Tjian R. "Redundant role of tissue-selective TAF(II)105 in B lymphocytes." Molecular and Cellular Biology, vol. 22, no. 18, 2002, pp. 6564-72. |
| Freiman RN, Albright SR, Zheng S, Sha WC, Hammer RE, Tjian R. "Requirement of tissue-selective TBP-associated factor TAFII105 in ovarian development." Science, vol. 293, no. 5537, 2001, pp. 2084-7. |
| Goto H, Motomura S, Wilson AC, Freiman RN, Nakabeppu Y, Fukushima K, Fujishima M, Herr W, Nishimoto T. "A single-point mutation in HCF causes temperature-sensitive cell-cycle arrest and disrupts VP16 function." Genes & Development, vol. 11, no. 6, 1997, pp. 726-37. |
| Sutton A, Freiman R. "The Cak1p protein kinase is required at G1/S and G2/M in the budding yeast cell cycle." Genetics, vol. 147, no. 1, 1997, pp. 57-71. |
| Freiman RN, Herr W. "Viral mimicry: common mode of association with HCF by VP16 and the cellular protein LZIP." Genes & Development, vol. 11, no. 23, 1997, pp. 3122-7. |
| Wilson AC, Freiman RN, Goto H, Nishimoto T, Herr W. "VP16 targets an amino-terminal domain of HCF involved in cell cycle progression." Molecular and Cellular Biology, vol. 17, no. 10, 1997, pp. 6139-46. |
| Cooper DA, Lu SC, Viswanath R, Freiman RN, Bensadoun A. "The structure and complete nucleotide sequence of the avian lipoprotein lipase gene." Biochimica et biophysica acta, vol. 1129, no. 2, 1992, pp. 166-71. |
| Seizinger BR, Smith DI, Filling-Katz MR, Neumann H, Green JS, Choyke PL, Anderson KM, Freiman RN, Klauck SM, Whaley J. "Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease." Proceedings of the National Academy of Sciences, vol. 88, no. 7, 1991, pp. 2864-8. |
| Chung R, Whaley J, Kley N, Anderson K, Louis D, Menon A, Hettlich C, Freiman R, Hedley-Whyte ET, Martuza R. "TP53 gene mutations and 17p deletions in human astrocytomas." Genes, chromosomes & cancer, vol. 3, no. 5, 1991, pp. 323-31. |
| Menon AG, Anderson KM, Riccardi VM, Chung RY, Whaley JM, Yandell DW, Farmer GE, Freiman RN, Lee JK, Li FP. "Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis." Proceedings of the National Academy of Sciences, vol. 87, no. 14, 1990, pp. 5435-9. |
Research
Research Overview
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.
Research Statement
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.
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.
Funded Research
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.
2R56HD065445-06A1 (PI: Freiman, R.N.) 02/08/2016-01/31/2018
NIH/NICHD Direct Costs: $198,896
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.
1R01 HD091848-01A1 (PI: Freiman, R.N.) 08/10/2018-05/31/2022
NIH/NICHD Direct Costs: $1,048,709
Dynamic Regulation of the Ovarian Reserve
The major goal of this project is to understand the cell type-specific and temporal functions and mechanisms of TAF4b in promoting the normal development of the mouse ovarian reserve.
Scholarly Work
- Spade DJ, Dere E, Hall SJ, Schorl C, Freiman, R.N. and Boekelheide K. (2018) All-trans retinoic acid disrupts development in ex vivo cultured fetal rat testes I: Altered seminiferous cord maturation and testicular cell fate. Toxicol Sci. Oct 17.doi: 10.1093/kfy260. PMID:30329139.
- Gura M and Freiman, RN. (2017) The primordial follicle. Encyclopedia of Reproduction, 2nd Edition, Elsevier.
- Grive KJ, Gustafson EA, Seymour KA, Baddoo M, Schorl C, Golnoski K, Rajkovic A, Brodsky AS and Freiman, RN. (2016) TAF4b regulates oocyte-specific genes essential for meiosis. PloS Genet. Jun 24;12(6):e1006128 doi:10.1371/journal.pgen1006128. PMID: 27341508. PMCID: PMC4920394.
- Lovasco LA, Gustafson EA, Seymour, KA, de Rooij, DG and RN Freiman. (2015). TAF4b is required for mouse spermatogonial stem cell development. Stem Cells Apr;33(4):1267-1276. PMID: 25727968. PMCID: PMC4376611.
- Brown CW, Brodsky AS and Freiman, RN. (2014) Notch3 Overexpression Promotes Anoikis Resistance in Epithelial Ovarian Cancer via Upregulation of COL4A2. Mol Cancer Res. Aug 28. PMID 25169943.
- Grive KJ, Seymour KA, Mehta R and Freiman, RN. (2014) TAF4b Promotes Mouse Primordial Follicle Assembly and Oocyte Survival. Dev Biol. Aug1;392(1):42-51. PMID 24836512.
- Ribeiro JR, Freiman RN. (2014) Estrogen signaling crosstalk: Implications for endocrine resistance in ovarian cancer. J Steroid Biochem Mol Biol. Feb 22;143C:160-173. PMID: 24565562.
- Ribeiro JR, Lovasco LA, Vanderhyden, BC and Freiman, RN. (2014) Targeting TBP-associated factors in ovarian cancer. Front Oncol. Mar 11; 4:45. PMID: 24653979.
- Freiman RN. Processing the complexities of transcription. (2013) Dev Cell. Oct 28;27(2):123-4. doi: 10.1016/j.devcel.2013.10.011. PMID: 24176636.
- Wardell JR, Hodgkinson KM, Binder AK, Seymour KA, Korach KS, Vanderhyden BC and Freiman RN. (2013) Estrogen Responsiveness of the TFIID Subunit TAF4B in the Normal Mouse Ovary and in Ovarian Tumors. Biol Reprod. 2013 Nov 14;89(5):116. PMID: 24068106.
- Reich A, Neretti N, Freiman RN, Wessel GM. (2012) Transcriptome variance in single oocytes within, and between, genotypes. Mol Reprod Dev. Aug;79(8):502-3. PMID: 22729953.
- 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.
Background
Education and Training
| Year | Degree | Institution |
|---|---|---|
| 1997 | PhD | State University of New York at Stony Brook |
| 1989 | BS | Cornell University |
Honors and Awards
- Dean's List, Cornell University
- Fellow of the Leukemia and Lymphoma Society
- Postdoctoral Research Fellow of the Howard Hughes Medical Institute
- New Scholar Award in Aging of the Ellison Medical Foundation
- Brown/NSF Advance Career Development Award
- Research Scholar Grant, American Cancer Society
- DMC Study Section Member, American Cancer Society
- CMIR Study Section Member, NIH
Affiliations
Affiliations
Society for the Study of Reproduction
American Association for Cancer Research
Teaching
Teaching
| BIOL 0500 - Cell and Molecular Biology |
| BIOL 1970A - Stem Cell Biology |
| BIOL 2050 - Biology of the Eukaryotic Cell |
| BIOL 2540 - Molecular Genetics |