Michael Grunstein, Ph.D.

A Short Biography:

Michael Grunstein is a Distinguished Professor Emeritus of Biological Chemistry at the Geffen School of Medicine at UCLA. He was born in Romania, obtained his BSc degree from McGill University in Montreal, the PhD degree from the University of Edinburgh, Scotland and did his post-doctoral training at Stanford University in Palo Alto, California where he invented the Colony Hybridization screening technique of recombinant DNAs in David Hogness's laboratory. Soon after coming to UCLA in 1975 he pioneered the genetic analysis of histones in yeast and showed for the first time that histones and histone modification sites are regulators of gene activity in living cells. His discovery led  to a new field of epigenetic study,  which investigates the role of histones and their modifications in the development of human diseases, including cancer

 


Work Titles
UCLA Distinguished Professor Emeritus, Biological Chemistry
Education:
Degrees:
Ph.D.
Academic Experience:
1975 - Dept MCDB and Dept Biological Chemistry
Honors and Awards:
2016 Gruber Genetics Prize (with David Allis)
2012 Thomson-Reuters Citation Laureate (with David Allis)
2011 Rosenstiel Award for Distinguished Work in Basic Medical Research (with David Allis)
2008 Elected to the National Academy of Sciences
2007 The 17th Beckman Symposium. The Changing Face of Chromatin
2006 Friedrich Miescher Institute, Basel, Science Colloquium Speaker
2005 Novum Lecture, Karolinska Institute, Stockholm
2004 Marian Koshland Lecturer, UC Berkeley
2003 Awarded Massry Prize (with Roger Kornberg and David Allis)
2001 International Scientific Advisory Board Member. Wellcome Trust Center for Cell Biology, University of Edinburgh, Scotland
2001 Elected Fellow of the American Academy of Arts and Science
2000 Swedish Royal Society of Sciences Lecture, Chromatin and Gene Expression
2000 Keynote Speaker, Euresco Conference, Gene Transcription in Yeast: Transcriptional Regulation and Chromatin Structure, Castelvecchio Pascoli, Italy
1999 Keynote Speaker, Chromatin Structure and Regulation, Keystone Symposium, Santa Fe, New Mexico
1998 MERIT Award, National Institutes of Health
1998 Markey Distinguished Speaker, University of Southern California
1995 Keynote Speaker, Keystone Symposium, Epigenetic Regulation of Transcription, Hilton Head Island, South Carolina
1994 Chair, Gordon Conference, Nuclear Proteins
1985 Chair, Chromosome Structure and Expression Conference, Cold Spring Harbor
1979 American Cancer Society Faculty Research Award
1976 Awardee March of Dimes Basil O'Connor Starter Research Grant
1972 Leukemia Society of America Fellow
1969 Wellcome Trust Studentship Award

Contact Information:

Work Phone Number:

(310) 825-0840

Office Address:

Boyer Hall Rm. 340, UCLA
611 Young Drive East,
Los Angels, CA 90095


Research Interest:

Michael Grunstein studies how histones and their post-translational modifications regulate chromosomal functions. It had been known since the 1960s that histone acetylation and gene activity were correlated but it was not known whether changes in chromatin structure and in particular histone acetylation are a cause or result of transcription. The Grunstein lab pioneered the use of genetics in analyzing histone protein function in yeast in the early 1980s. This analysis was to show that nucleosomes are repressors of transcription initiation in living cells and that acetylation sites at the histone N termini are required for gene activity. Moreover his lab demonstrated in 1995 that non-histone regulatory proteins bind histones to regulate heterochromatin formation. This allowed the lab to determine how an acetylation site (histone H4 K16) at the H4 N terminus regulates the initiation, spreading and the barrier to spreading of heterochromatin.

At present the Grunstein laboratory uses genetics, genome wide and gene specific biochemical approaches to study how histones regulate the binding of regulatory enzymes and structural factors to chromatin. His lab's findings include the role of histone deacetylation in regulating the timing of DNA replication, the role of deacetylation in gene activity and the genome wide division of labor for histone deacetylases and histone acetylation sites in yeast. Recent studies from the Grunstein lab have uncovered the acetylation of a novel site histone H3 K56 in yeast and its role in transcription and heterochromatin silencing. The modification of this site that also regulates yeast histone assembly, DNA replication and DNA repair is currently a focus of the lab in studying the differentiation of human stem cells.

Michael Grunstein studies how histones and their post-translational modifications regulate chromosomal functions. It had been known since the 1960s that histone acetylation and gene activity were correlated but it was not known whether changes in chromatin structure and in particular histone acetylation are a cause or result of transcription. The Grunstein lab pioneered the use of genetics in analyzing histone protein function in yeast in the early 1980s. This analysis was to show that nucleosomes are repressors of transcription initiation in living cells and that acetylation sites at the histone N termini are required for gene activity. Moreover his lab demonstrated in 1995 that non-histone regulatory proteins bind histones to regulate heterochromatin formation. This allowed the lab to determine how an acetylation site (histone H4 K16) at the H4 N terminus regulates the initiation, spreading and the barrier to spreading of heterochromatin.

At present the Grunstein laboratory uses genetics, genome wide and gene specific biochemical approaches to study how histones regulate the binding of regulatory enzymes and structural factors to chromatin. His lab's findings include the role of histone deacetylation in regulating the timing of DNA replication, the role of deacetylation in gene activity and the genome wide division of labor for histone deacetylases and histone acetylation sites in yeast. Recent studies from the Grunstein lab have uncovered the acetylation of a novel site histone H3 K56 in yeast and its role in transcription and heterochromatin silencing. The modification of this site that also regulates yeast histone assembly, DNA replication and DNA repair is currently a focus of the lab in studying the differentiation of human stem cells.

Detailed Biography:

Michael Grunstein is Distinguished Professor of Biological Chemistry at the Geffen School of Medicine at UCLA. He was born in Romania, obtained his BSc degree from McGill University in Montreal, the PhD degree from the University of Edinburgh, Scotland and did his post-doctoral training at Stanford University in Palo Alto, California where he invented the Colony Hybridization screening technique of recombinant DNAs in David Hogness's laboratory. Soon after coming to UCLA in 1975 he pioneered the genetic analysis of histones in yeast and showed for the first time that histones are regulators of gene activity in living cells. He now studies the means by which histone modifications regulate gene activity and DNA replication in yeast, mouse and human cells.

Publications:

Tan Yuliang, Xue Yong, Song Chunying, Grunstein Michael   Acetylated histone H3K56 interacts with Oct4 to promote mouse embryonic stem cell pluripotency Proceedings of the National Academy of Sciences of the United States of America, 2013; 110(28): 11493-8.
Grunstein Michael, Gasser Susan M   Epigenetics in Saccharomyces cerevisiae Cold Spring Harbor perspectives in biology, 2013; 5(7): .
Yu Yongxin, Song Chunying, Zhang Qiongyi, DiMaggio Peter A, Garcia Benjamin A, York Autumn, Carey Michael F, Grunstein Michael   Histone H3 lysine 56 methylation regulates DNA replication through its interaction with PCNA Molecular Cell, 2012; 46(1): 7-17.
Kitada Tasuku, Kuryan Benjamin G, Tran Nancy Nga Huynh, Song Chunying, Xue Yong, Carey Michael, Grunstein Michael   Mechanism for epigenetic variegation of gene expression at yeast telomeric heterochromatin Genes & development, 2012; 26(21): 2443-55.
Chen Xiao-Fen, Kuryan Benjamin, Kitada Tasuku, Tran Nancy, Li Jing-Yu, Kurdistani Siavash, Grunstein Michael, Li Bing, Carey Michael   The Rpd3 core complex is a chromatin stabilization module Current biology : CB, 2012; 22(1): 56-63.
Adam S. Sperling, Kyeong Soo Jeong, Tasuku Kitada and Michael Grunstein   Topoisomerase II binds nucleosome-free DNA and acts redundantly with Topoisomerase I to enhance recruitment of RNA Pol II in budding yeast , Proc. Nat. Acad. Sci. USA, 2011; 108: 12693-8.
Kitada, T., Schleker, T., Sperling. A.S., Xie, W., Gasser, S.M. and Grunstein, M.   gH2A is a component of yeast heterochromatin required for telomere elongation, Cell Cycle, 2011; 10(2): 1-8.
Indranil Sinha, Luke Buchanan, Carolina Bonilla, Michelle Rönnerblad, Andrej Shevchenko, Michael Grunstein, A. Francis Stewart and Karl Ekwall   Genome wide mapping of histone modifications and mass spectrometry reveal a function for the histone H4 acetylation zip and a role for H3K36 methylation at gene promoters in fission yeast, Epigenomics, 2010; 2: 377-393.
Sun W, Xie W, Xu F, Grunstein M, Li KC.   Dissecting nucleosome free regions by a segmental semi-Markov model. , PLoS ONE, 2009; 4(3): e4721. Epub 2009 Mar 6..
Xie, W., Song, C., Sperling, A., Xu, F., Sridharan, R., Conway, A., Plath, K., Clark, A., and Grunstein, M.   Histone H3 K56 acetylation is linked to the core transcriptional network for pluripotency in human embryonic stem cells, Molecular Cell , 2009; 33: 417-427.
Sperling, A. and Grunstein, M.   Histone H3 N-terminus regulates higher order structure of yeast heterochromatin. , PNAS , 2009; 106: 13153-13159 .
Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, Ambartsumyan G, Aimiuwu O, Richter L, Zhang J, Khvorostov I, Ott V, Grunstein M, Lavon N, Benvenisty N, Croce CM, Clark AT, Baxter T, Pyle AD, Teitell MA, Pelegrini M, Plath K, Lowry WE.   Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures, Cell Stem Cell, 2009; 5: 111-23.
Jonathan Houseley, Liudmilla Rubbi, Michael Grunstein, David Tollervey, and Maria Vogelauer   A ncRNA Modulates Histone Modification and mRNA Induction in the Yeast GAL Gene Cluster, Molecular Cell, 2008; 32: 685-695.
Gregory A. Horwitz, Kangling Zhang, Matthew A. McBrian, Michael Grunstein, Siavash K. Kurdistani, & Arnold J. Berk   Adenovirus small e1a alters global patterns of histone modification. , Science , 2008; 321: 1084-1085.
Tommy Kaplan, Chih Long Liu, Judith A. Erkmann, John Holik, Michael Grunstein, Paul D. Kaufman, Nir Friedman, Oliver J. Rando   Cell Cycle– and Chaperone-Mediated Regulation of H3K56ac Incorporation in Yeast. , PLoS Genetics , 2008; 4(11 ): 1-16. Publ.on-line..
Sahbazian, M. D. and Grunstein, M.   Functions of site-specific histone acetylation and deacetylation. , Annual Reviews of Biochemistry, 2007; 76: 26.1-26.26.
Xu, F., Zhang, Q., Zhang, K., Xie, W. and Grunstein, M.   Sir2 deacetylates histone H3 lysine 56 to regulate telomeric heterochromatin structure in yeast , Molecular Cell, 2007; 27: 890-900.
Mickael Durand-Dubief, Indranil Sinha, Fredrik Fagerstrom-Billai, Carolina Bonilla, Anthony Wright, Michael Grunstein, Karl Ekwall   Specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation and retrotransposon silencing , EMBO J. , 2007; 26: 2477-2488.
Millar CB, Xu F, Zhang K, Grunstein M   Acetylation of H2AZ lysine 14 is associated with genome-wide gene activity in yeast, Genes and Development, 2006; 20: 711-722.
Grunstein M, Gasser S   Epigenetics in Saccharomyces cerevisiae: Chapter 4, Epigenetics , 2006; 63-79.
Millar CB, Grunstein M   Genome wide patterns of histone modifications in yeast, Nature Reviews Molecular Cell Biology, 2006; 7: 657-666.
Ahn, S., Diaz, R. L. Grunstein, M. and Allis, C. D.   Histone H2B deacetylation at lysine 11 is required for yeast apoptosis induced by phosphorylation of H2B at serine 10. , Molecular Cell, 2006; 24: 211-220.
Xu F, Zhang K, Grunstein M   Acetylation in histone H3 globular domain regulates gene expression in yeast Cell. , 2005; 121(3): 375-85.
Xu, F., Zhang, K. and Grunstein, M.   Acetylation in the histone H3 globular domain regulates gene expression in yeast, Cell, 2005; 121: 375-385.
Keogh MS, Kurdistani SK, Morris SA, Ahn SH, Collins SR, Podolny V, Chin K, Punna T, Thompson NJ, Boone C, Emili A, Weissman JS, Hughes TR, Strahl BD, Grunstein M, Greenblatt JF, Buratowski S, Krogan NJ   Co-transcriptional Set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex, Cell, 2005; 123: 593-605.
Wiren M, Silverstein R, Sinha I, Walfridsson J, Lee H, Laurenson P, Pillus L, Robyr D, Grunstein M, Ekwall K   Genome wide analysis of nucleosome density, histone acetylation and HDAC function in fission yeast , EMBO J. , 2005; 24: 2906-2918.
Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK   Global histone modification patterns predict risk of prostate cancer recurrence Nature. , 2005; 435(7046): 1262-6.
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Shahbazian MD, Zhang K, Grunstein M   Histone H2B ubiquitylation is dispensable for mono-methylation but important for subsequent rounds of methylation by Dot1 and Set1, Molecular Cell, 2005; 19: 271-277.
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Robyr D, Kurdistani SK, Grunstein M   Analysis of genome-wide histone acetylation state and enzyme binding using DNA microarrays Methods in enzymology. , 2004; 376: 289-304.
Kurdistani SK, Tavazoie S, Grunstein M   Mapping global histone acetylation patterns to gene expression Cell. , 2004; 117(6): 721-33.
Robyr D, Kurdistani SK, Grunstein M (2003)   Analysis of genome-wide histone , Methods In Enzymology, 2003; 376: 289-304.
Mellone BG, Ball L, Suka N, Grunstein MR, Partridge JF, Allshire RC   Centromere silencing and function in fission yeast is governed by the amino terminus of histone H3 Current biology : CB. , 2003; 13(20): 1748-57.
Robyr D, Grunstein M   Genomewide histone acetylation microarrays Methods (San Diego, Calif.) , 2003; 31(1): 83-9.
Kurdistani SK, Grunstein M   Histone acetylation and deacetylation in yeast Nat Rev Mol Cell Biol, 2003; 4(4): 276-84.
Kurdistani SK, Grunstein M   In vivo protein-protein and protein-DNA crosslinking for genomewide binding microarray Methods (San Diego, Calif.) , 2003; 31(1): 90-5.
Carmen AA, Milne L, Grunstein M   Acetylation of the yeast histone H4 N terminus regulates its binding to heterochromatin protein SIR3 The Journal of biological chemistry. , 2002; 277(7): 4778-81.
Kurdistani SK, Robyr D, Tavazoie S, Grunstein M   Genome-wide binding map of the histone deacetylase Rpd3 in yeast Nature genetics. , 2002; 31(3): 248-54.
Vogelauer M, Rubbi L, Lucas I, Brewer BJ, Grunstein M   Histone acetylation regulates the time of replication origin firing Molecular cell. , 2002; 10(5): 1223-33.
Robyr D, Suka Y, Xenarios I, Kurdistani SK, Wang A, Suka N, Grunstein M   Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases Cell. , 2002; 109(4): 437-46.
Wang A, Kurdistani SK, Grunstein M   Requirement of Hos2 histone deacetylase for gene activity in yeast Science. , 2002; 298(5597): 1412-4.
Kristjuhan A, Walker J, Suka N, Grunstein M, Roberts D, Cairns BR, Svejstrup JQ   Transcriptional inhibition of genes with severe histone h3 hypoacetylation in the coding region Molecular cell. , 2002; 10(4): 925-33.
Wu J, Carmen AA, Kobayashi R, Suka N, Grunstein M   HDA2 and HDA3 are related proteins that interact with and are essential for the activity of the yeast histone deacetylase HDA1 Proceedings of the National Academy of Sciences of the United States of America. , 2001; 98(8): 4391-6.
Suka N, Suka Y, Carmen AA, Wu J, Grunstein M   Highly specific antibodies determine histone acetylation site usage in yeast heterochromatin and euchromatin Molecular cell. , 2001; 8(2): 473-9.
Wu J, Suka N, Carlson M, Grunstein M   TUP1 utilizes histone H3/H2B-specific HDA1 deacetylase to repress gene activity in yeast Molecular cell. , 2001; 7(1): 117-26.
Wu J, Grunstein M   25 years after the nucleosome model: chromatin modifications Trends in biochemical sciences. , 2000; 25(12): 619-23.
Clark WR, Grunstein M   Are we hardwired? The role of genes in human behavior. Oxford Univ. Press. N.Y., N.Y, , 2000; 1st Edition: .
Vogelauer M, Wu J, Suka N, Grunstein M   Global histone acetylation and deacetylation in yeast, Nature, 2000; 408: 495-498.
Free A, Grunstein M, Bird A, Vogelauer M   Histone deacetylation: Repressor Mechanisms, Chromatin Structure and Gene Expression. Frontiers in Molecular Biology, 2000; 2nd Edition: .
Wyrick JJ, Holstege FC, Jennings EG, Causton HC, Shore D, Grunstein M, Lander ES, Young RA   Chromosomal landscape of nucleosome-dependent gene expression and silencing in yeast Nature. , 1999; 402(6760): 418-21.
Kadonaga JT, Grunstein M   Chromosomes and Expression Mechanisms, Current Opinion in Genetics and Development, 1999; Vol. 9 no. 2, April: .
Martin SG, Laroche T, Suka N, Grunstein M, Gasser SM   Relocalization of telomeric Ku and SIR proteins in response to DNA strand breaks in yeast Cell. , 1999; 97(5): 621-33.
Carmen AA, Griffin PR, Calaycay JR, Suka N, Grunstein M   Yeast HOS3 forms a novel TSA-insensitive homodimer with intrinsic catalytic activity, Proc. Nat. Acad. Sci. USA, 1999; 96: 12356-12361.
Ma X-J, Wu J, Altheim A, Schultz MC, Grunstein M   Deposition-related sites K5/K12 in histone H4 are not required for nucleosome deposition in yeast, Proc. Nat. Acad. Sci. USA, 1998; 95: 6693-6698.
Rundlett SE, Carmen AA, Suka N, Turner BM, Grunstein M   Transcriptional repression by UME6 involves deacetylation of lysine 5 of histone H4 by RPD3 Nature. , 1998; 392(6678): 831-5.
Grunstein M   Histone acetylation in chromatin structure and transcription, Nature, 1997; 389: 349-352.
Strahl-Bolsinger S, Hecht A, Luo K, Grunstein M   SIR2 and SIR4 interactions differ in core and extended telomeric heterochromatin in yeast Genes & development. , 1997; 11(1): 83-93.
Ma X, Lu Q, Grunstein M   A search for proteins that interact genetically with histone H3 and H4 N-termini uncovers novel regulators of the Swe 1 kinase in Saccharomyces cerevisiae, Genes and Development, 1996; 10: 1327-1340.
Lenfant F, Mann RK, Thomsen B, Ling X, Grunstein M   All four core histone N-termini contain sequences required for the repression of basal transcription in yeast The EMBO journal. , 1996; 15(15): 3974-85.
Carmen AA, Rundlett SE, Grunstein M   HDA1 and HDA3 are components of a yeast histone deacetylase (HDA) complex The Journal of biological chemistry. , 1996; 271(26): 15837-44.
Rundlett SE, Carmen AA, Kobayashi R, Bavykin S, Turner BM, Grunstein M   HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription Proceedings of the National Academy of Sciences of the United States of America. , 1996; 93(25): 14503-8.
Hecht A, Strahl-Bolsinger S, Grunstein M   Spreading of transcriptional repressor SIR3 from telomeric heterochromatin Nature. , 1996; 383(6595): 92-6.
Ling X, Harkness TAA, Schultz MC, Fisher-Adams G, Grunstein M   Yeast histone H3 and H4 N-termini are important for nucleosome assembly in vivo and in vitro, Genes and Development, 1996; 10: 686-699.
Hecht A, Laroche T, Strahl-Bolsinger S, Gasser SM, Grunstein M   Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast Cell. , 1995; 80(4): 583-92.
Wan JS, Mann RK, Grunstein M   Yeast histone H3 and H4 N termini function through different GAL1 regulatory elements to repress and activate transcription Proceedings of the National Academy of Sciences of the United States of America. , 1995; 92(12): 5664-8.
Fisher-Adams G, Grunstein M   Yeast histone H4 and H3 N-termini have different effects on the chromatin structure of the GAL1 promoter The EMBO journal. , 1995; 14(7): 1468-77.
Thompson JS, Ling X, Grunstein M   Histone H3 amino terminus is required for telomeric and silent mating locus repression in yeast Nature. , 1994; 369(6477): 245-7.
Mann RK, Grunstein M   Histone H3 N-terminal mutations allow hyperactivation of the yeast GAL1 gene in vivo The EMBO journal. , 1992; 11(9): 3297-306.
Grunstein M   Histones as regulators of genes, Scientific American, 1992; 267: 68-74.
Johnson LM, Fisher-Adams G, Grunstein M   Identification of a non-basic domain in the histone H4 N-terminus required for repression of the yeast silent mating loci The EMBO journal. , 1992; 11(6): 2201-9.
Durrin LK, Mann RK, Kayne PS, Grunstein M   Yeast histone H4 N-terminal sequence is required for promoter activation in vivo Cell. , 1991; 65(6): 1023-31.
Johnson LM, Kayne PS, Kahn ES, Grunstein M   Genetic evidence for an interaction between SIR3 and histone H4 in the repression of the silent mating loci in Saccharomyces cerevisiae Proceedings of the National Academy of Sciences of the United States of America. , 1990; 87(16): 6286-90.
Grunstein M   Histone function in transcription, Annual Reviews of Cell Biology, 1990; 6: 643-678.
Han M, Kim UJ, Kayne P, Grunstein M   Depletion of histone H4 and nucleosomes activates the PHO5 gene in Saccharomyces cerevisiae The EMBO journal. , 1988; 7(7): 2221-8.
Kayne PS, Kim UJ, Han M, Mullen JR, Yoshizaki F, Grunstein M   Extremely conserved histone H4 N terminus is dispensable for growth but essential for repressing the silent mating loci in yeast Cell. , 1988; 55(1): 27-39.
Han M, Grunstein M   Nucleosome loss activates yeast downstream promoters in vivo Cell. , 1988; 55(6): 1137-45.
Schuster T, Han M, Grunstein M   Yeast histone H2A and H2B amino termini have interchangeable functions Cell. , 1986; 45(3): 445-51.
Travis GH, Colavito-Shepanski M, Grunstein M   Extensive purification and characterization of chromatin-bound histone acetyltransferase from Saccharomyces cerevisiae The Journal of biological chemistry. , 1984; 259(23): 14406-12.
Wallis JW, Rykowski M, Grunstein M   Yeast histone H2B containing large amino terminus deletions can function in vivo Cell. , 1983; 35(3 Pt 2): 711-9.
Rykowski MC, Wallis JW, Choe J, Grunstein M   Histone H2B subtypes are dispensable during the yeast cell cycle Cell. , 1981; 25(2): 477-87.
Wallis JW, Hereford L, Grunstein M   Histone H2B genes of yeast encode two different proteins Cell. , 1980; 22(3): 799-805.
Grunstein M, Hogness DS   Colony hybridization: a method for the isolation of cloned DNAs that contain a specific gene Proceedings of the National Academy of Sciences of the United States of America. , 1975; 72(10): 3961-5.

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