John Sedivy is recognized for his efforts in mammalian cell genetics, having developed and pioneered methods for gene targeting of somatic cells. In 1995 his laboratory isolated the first viable gene knockout of the c-Myc oncogene, and in 1997 the first homozygous gene knockout in a normal human cell. Since 1998 his research has focused on understanding the biology of aging at the cellular level. These projects currently investigate the epigenetic regulation of cellular senescence, genome-wide surveillance of transposable elements, and the role of c-Myc in aging.

Biography

Professor John Sedivy joined the Brown Faculty in 1996 and is a member of the Department of Molecular Biology, Cell Biology and Biochemistry. He obtained his PhD from Harvard in 1985, and subsequently trained with the Nobel Laureate Philip Sharp at the MIT Center for Cancer Research. He started his independent research career at Yale University in 1988.

John Sedivy's research on cell cycle regulation and signal transduction, focusing initially on the Myc oncogene and subsequently on replicative senescence (cellular aging), has been continuously funded by the National Institutes of Health since 1989. In 2003 he became interested in genomics, and his work on Myc-regulated gene networks led to an involvement in bioinformatics and systems biology. In 2004 his lab started work on single-cell assays of cellular senescence by developing a robust biomarker of telomere-initiated senescence. Using this assay they delineated the signaling pathways between dysfunctional telomeres and the cell cycle, and in 2006 published the first comprehensive in vivo quantification of cellular senescence in aging primates. In 2006 they also discovered that c-Myc contributes to the regulation of chromatin states though the Polycomb pathway, initiating their entry into epigenetics. This led to the development of single-cell assays showing age-associated in vivo expansion of heterochromatin, and current studies of genome-wide chromatin changes in cellular senescence as well as organismal aging.

In addition to writing the first comprehensive book on gene targeting in 1992, John Sedivy has published over 130 original articles. He has served on numerous study sections and advisory committees at the National Institutes of Health, the American Cancer Society, and the US Army Breast Cancer Initiative. He has consulted extensively on the genetic manipulation of mammalian cells to the biotech industry, including Biogen, Eli Lilly & Co., Abbott Laboratories, and Millenium Pharmaceuticals. He maintains an active role in the field of aging, as a founding member (and current chair) of the CMAD study section at the National Institutes of Health, co-Editor-in-Chief of the journal Aging Cell, and chair of the 2015 Gordon Research Conference on the Biology of Aging. He has fulfilled major administrative leadership roles at Brown University, including chairing the Department of Molecular Biology, Cell Biology and Biochemistry, and founding an academic center for Genomics and Proteomics.

Institutions

BU

Awards

1974 Ontario Scholar
1981 Ryan Foundation Fellow
1989 March of Dimes Basil O'Connor Starter Scholar
1990 Presidential Young Investigator
1991 Andrew Mellon Award
2006 Hermon C. Bumpus Endowed Chair in Biology, Brown University
2007 Senior Research Scholar in Aging, Ellison Medical Foundation
2009 NIH Merit Award, National Institute on Aging
2011 Glenn Award for Research in Biological Mechanisms of Aging
2015 Chair, Gordon Research Conference on the Biology of Aging

Affiliations

1990-present American Society for Microbiology (ASM), Member
1993-present American Association for Cancer Research (AACR), Member
2002-present American Society for Biochemistry and Molecular Biology (ASBMB), Member
1994-2001 US Army Breast Cancer Initiative, Member, Scientific Advisory Committee, MBG Study Sections
1996-2001 American Cancer Society (ACS), Member, Peer Review Committee, DDC Study Section
1998-present Organizer, Colloquium on the Biology of Human Aging, Brown University
2000-2003 National Institutes of Health (NIH), Member, Scientific Review Group, CDF-2 Study Section
2001-2004 Editorial Board, Journal of Molecular Medicine
2001-2007 Advanced Cell Technology, Inc., Worcester, MA, Scientific Advisory Board Member
2001-present Biolog, Inc., Hayward, CA, Scientific Advisory Board Member
2002-2005 Section Editor, Aging Cell
2002 Organizer, Banbury Center Conference on Cellular Immortalization, Cold Spring Harbor, NY
2003-present Editor, Experimental Cell Research
2003-2004 NIH, Member, Scientific Review Group, CMAD Study Section
2006-2012 Co-Editor-in-Chief, Aging Cell
2009-present NIH, Member, Scientific Review Group, CMAD Study Section
2009 NIH, Member, National Advisory Council on Aging, Division of Aging Biology
2010-present Editorial Board, Cell Cycle
2012-present Reviews Editor, Aging Cell
2012-2014 NIH, Chair, Scientific Review Group, CMAD Study Section

Funded Research

Ongoing Research Support

R37 AG016694-13 (PI: Sedivy, J.M.) 05/01/09-04/30/14
NIH/NIA
Effectors of cellular senescent states.
The major goals of this project are to investigate biological parameters that correlate with and functionally influence telomere-initiated cellular senescence in vivo, to develop single-cell assays to measure chromatin reorganization, and to investigate heterochromatin-associated senescence states in vivo, and to discover what causes the stochastic, telomere-independent upregulation of p16.
Role: PI

R01 AG035328-03 (PI: Sedivy, J.M.) 10/01/09-09/30/13
NIH/NIA
The Wnt-chromatin axis in aging.
The goals of this project are to investigate the role of decreased Wnt signaling in cell culture and mouse models as an initiator of replicative cellular senescence.
Role: PI

No number (PI: Sedivy, J.M.) 08/01/11-07/31/13
Private/Glenn Foundation for Medical Research
Glenn Award for Research in Biological Mechanisms of Aging.
This is a one time unrestricted award to augment aging research in Dr. Sedivy's laboratory.
Role: PI

P30 RR031153-02 (PI: Atwood, W.) 04/15/11-04/14/16
NIH/NCRR
Center for Cancer Signaling Networks.
This award funds several interdisciplinary projects and core facilities in a Center of Biomedical Research Excellence (COBRE). Dr. Sedivy provides services as the Director of the Genomics Core Facility; other than a fraction of his salary this award does not fund projects in his laboratory.
Role: Core Facility Director

T32 AG041688-01 (PI: Sedivy, J.M.) 07/01/12-06/30/17
NIH/NIA
Predoctoral Training in the Molecular Biology of Aging
This institutional training grant will support the stipends and tuition of predoctoral students in a curricular track focused on the biology of aging.
Role: PI

View My Full Publication List in pdf format

Selected Publications

• De Cecco, M., Criscione, S.W., Peckham, E.J., Hillenmeyer, S., Hamm, E.A., Manivannan, J., Peterson, A.L., Kreiling, J.A., Neretti, N. and Sedivy, J.M. (2013). Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12: 247-256 (PMID 23360310; PMCID 3618682).(2013)
• Kreiling, J.A., Tamamori-Adachi, M., Sexton, A.N., Jeyapalan, J.C., Munoz-Najar, U., Peterson, A.L., Manivannan, J., Rogers, E.S., Pchelintsev, N.A., Adams, P.D. and Sedivy, J.M. (2011). Age-associated increase in heterochromatic marks in murine and primate tissues. Aging Cell 10: 292-304 (PMID: 21176091; PMCID 3079313).(2011)
• Guney, I., Wu, S. and Sedivy, J.M. (2006). Reduced c-Myc signaling triggers telomere-independent senescence by regulating the polycomb repressor Bmi-1 and the CDK inhibitor p16INK4a. Proc. Natl. Acad. Sci. USA 103: 3645-3650 (PMID: 16537449).(2006)
• Herbig, U., Ferreira, M., Condel, L., Carey, D. and Sedivy, J.M. (2006). Cellular senescence in aging primates. Science 311: 1257 (PMID: 16456035).(2006)
• Remondini, D., O'Connell, B., Intrator, N., Sedivy, J.M., Neretti, N., Castellani, G.C. and Cooper, L.N. (2005). Targeting c-Myc activated genes via a correlation method: detection of global changes in large gene expression network dynamics. Proc. Natl. Acad. Sci. USA 102: 6902-6906.(2005)
• Herbig, U., Jobling, W.A., Chen, B.P.C., Chen, D.J. and Sedivy, J.M. (2004). Telomere shortening triggers replicative senescence of human cells through a signaling pathway involving ATM, p53 and p21CIP1 but not p16INK4a. Mol. Cell 14: 501-513.(2004)
• Wei, W., Jobling, W.A., Chen, W., Hahn, W.C. and Sedivy, J.M. (2003). Abolition of cyclin-dependent kinase inhibitors p16Ink4a and p21Cip1/Waf1 functions permits Ras-induced anchorage-independent growth in telomerase-immortalized human fibroblasts. Mol. Cell. Biol. 23: 2859-2870.(2003)
• Yeung, K.C., Rose, D.W., Dhillon, A.S., Yaros, D., Gustafsson, M., Chatterjee, D., McFerran, B., Wyche, J., Kolch, W. and Sedivy, J.M. (2001). Raf kinase inhibitor protein interacts with NF-κB-inducing kinase and TAK1 and inhibits NF-κB activation. Mol Cell. Biol. 21: 7207-7217.(2001)
• Wei, W., Hemmer, R.M. and Sedivy, J.M. (2001). The role of p14ARF in replicative and induced senescence of human fibroblasts. Mol. Cell. Biol. 21: 6748-6757.(2001)
• Adachi, S., Obaya, A.J., Han, Z., Ramos-Desimone, N., Wyche, J.H. and Sedivy, J.M. (2001). c-Myc is necessary for DNA damage-induced apoptosis in the G2 phase of the cell cycle. Mol. Cell. Biol. 21: 4929-4937.(2001)
• Yeung, K.C., Seitz, T., Li, S., Janosch, P., McFerran, B., Kaiser, C., Fee, F., Katsanakis, K.D., Rose, D.W., Mischak, H., Sedivy, J.M. and Kolch, W. (1999). Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 401: 173-177.(1999)
• Mateyak, M.K., Obaya, A.J. and Sedivy, J.M. (1999). c-Myc regulates cyclin D/Cdk4/6 activity but affects cell cycle progression at multiple independent steps. Mol. Cell. Biol. 19: 4672-4683.(1999)
• Brown, J.P., Wei, W. and Sedivy, J.M. (1997). Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277: 831-834.(1997)
• Hanson, K.D., and Sedivy, J.M. (1995). Analysis of biological selections for high efficiency gene targeting. Mol. Cell. Biol. 15: 45-51.(1995)
• Sedivy, J.M. and Sharp, P.A. (1989). Positive genetic selection for gene disruption in mammalian cells by homologous recombination. Proc. Natl. Acad. Sci. USA 86: 227-231.(1989)
• Sedivy, J.M., Capone, J.P., RajBhandary, U.L. and Sharp, P.A. (1987). An inducible mammalian amber suppressor: propagation of a poliovirus mutant. Cell 50: 379-389.(1987)