Affiliations

Chair and Associate Professor, Biological Chemistry

Member, Cell & Developmental Biology GPB Home Area, Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, Gene Regulation GPB Home Area, JCCC Gene Regulation Program Area, themes

Faculty, Cellular and Molecular Pathology PhD Program

Chromatin is a highly condensed complex of nucleic acid and basic proteins whose fundamental subunit, the nucleosome, has the same type of design in all eukaryotes. The nucleosome contains ~200 bp of DNA wrapped around an octamer of histones consisting of two copies of each histone H2A, H2B, H3 and H4. All histones are modified by covalent linkage of extra chemical moieties to the free groups of certain amino acids. Examples include acetylation and methylation of lysines, methylation of arginines and phosphorylation of serines. These modifications are transient and able to change the functional properties of the chromatin fiber, thereby affecting all cellular processes that are based on DNA such as transcription. Until recently, most studies of histone modifications have been by-and-large reductionist, focusing on individual promoters. While these studies have revealed important principles, a more comprehensive understanding of chromatin requires that we ascend in scale to genome-wide views to discern biological elements that are not apparent in gene-by-gene surveys. The overall goal of our laboratory is to understand the dynamics, establishment and maintenance mechanisms of histone modifications on a global scale. We use the yeast Saccharomyces cerevisiae as a model organism and combine standard biochemistry, molecular biology, and genetic protocols with high throughput techniques such as DNA microarrays to simultaneously assay histone modifications throughout the genome. Preliminary evidence from our genome-wide studies suggests that we need to develop novel conceptual frameworks for integrating such global knowledge into a predictive model of chromatin biology. We are also interested in applying the lessons learned in yeast to higher eukaryotes. Such transition is straightforward due to the very high degree of conservation of both histone modifications and the relevant enzymes. Using the tools developed in yeast, we have recently shown that combinatorial patterns of histone modification are predictors of clinical outcome in prostate cancer.

McBrian Matthew A, Behbahan Iman Saramipoor, Ferrari Roberto, Su Trent, Huang Ta-Wei, Li Kunwu, Hong Candice S, Christofk Heather R, Vogelauer Maria, Seligson David B, Kurdistani Siavash K Histone Acetylation Regulates Intracellular pH. Molecular cell. 2013; 49(2): 310-21. Li Jing-Yu, Patterson Michaela, Mikkola Hanna K A, Lowry William E, Kurdistani Siavash K Dynamic distribution of linker histone H1.5 in cellular differentiation. PLoS genetics. 2012; 8(8): e1002879. Kurdistani Siavash K Enhancer dysfunction: how the main regulators of gene expression contribute to cancer. Genome biology. 2012; 13(5): 156. Chen Xiao-Fen, Lehmann Lynn, Lin Justin J, Vashisht Ajay, Schmidt Ryan, Ferrari Roberto, Huang Chengyang, McKee Robin, Mosley Amber, Plath Kathrin, Kurdistani Siavash K, Wohlschlegel James, Carey Michael Mediator and SAGA have distinct roles in Pol II preinitiation complex assembly and function. Cell reports. 2012; 2(5): 1061-7. Lehmann Lynn, Ferrari Roberto, Vashisht Ajay A, Wohlschlegel James A, Kurdistani Siavash K, Carey Michael Polycomb repressive complex 1 (PRC1) disassembles RNA polymerase II preinitiation complexes. The Journal of biological chemistry. 2012; 287(43): 35784-94. Ferrari Roberto, Su Trent, Li Bing, Bonora Giancarlo, Oberai Amit, Chan Yvonne, Sasidharan Rajkumar, Berk Arnold J, Pellegrini Matteo, Kurdistani Siavash K Reorganization of the host epigenome by a viral oncogene. Genome research. 2012; 22(7): 1212-21. Van Handel Ben, Montel-Hagen Amélie, Sasidharan Rajkumar, Nakano Haruko, Ferrari Roberto, Boogerd Cornelis J, Schredelseker Johann, Wang Yanling, Hunter Sean, Org Tõnis, Zhou Jian, Li Xinmin, Pellegrini Matteo, Chen Jau-Nian, Orkin Stuart H, Kurdistani Siavash K, Evans Sylvia M, Nakano Atsushi, Mikkola Hanna K A Scl represses cardiomyogenesis in prospective hemogenic endothelium and endocardium. Cell. 2012; 150(3): 590-605. Vogelauer Maria, Krall Abigail S, McBrian Matthew A, Li Jing-Yu, Kurdistani Siavash K Stimulation of histone deacetylase activity by metabolites of intermediary metabolism. The Journal of biological chemistry. 2012; 287(38): 32006-16. 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. Marban Céline, Su Trent, Ferrari Roberto, Li Bing, Vatakis Dimitrios, Pellegrini Matteo, Zack Jerome A, Rohr Olivier, Kurdistani Siavash K Genome-wide binding map of the HIV-1 Tat protein to the human genome. PloS one. 2011; 6(11): e26894. Kurdistani Siavash K Histone modifications in cancer biology and prognosis. Progress in drug research. Fortschritte der Arzneimittelforschung. Progrès des recherches pharmaceutiques. 2011; 67(11): 91-106. Seligson David B, Horvath Steve, McBrian Matthew A, Mah Vei, Yu Hong, Tze Sheila, Wang Qun, Chia David, Goodglick Lee, Kurdistani Siavash K Global levels of histone modifications predict prognosis in different cancers. The American journal of pathology. 2009; 174(5): 1619-28. Gekas Christos, Rhodes Katrin E, Gereige Laurraine M, Helgadottir Hildur, Ferrari Roberto, Kurdistani Siavash K, Montecino-Rodriguez Encarnación, Bassel-Duby Rhonda, Olson Eric, Krivtsov Andrei V, Armstrong Scott, Orkin Stuart H, Pellegrini Matteo, Mikkola Hanna K A Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis. Blood. 2009; 113(15): 3461-71. Ferrari Roberto, Berk Arnold J, Kurdistani Siavash K Viral manipulation of the host epigenome for oncogenic transformation. Nature reviews. Genetics. 2009; 10(5): 290-4. Horwitz Gregory A, Zhang Kangling, McBrian Matthew A, Grunstein Michael, Kurdistani Siavash K, Berk Arnold J Adenovirus small e1a alters global patterns of histone modification. Science (New York, N.Y.). 2008; 321(5892): 1084-5. Ferrari Roberto, Pellegrini Matteo, Horwitz Gregory A, Xie Wei, Berk Arnold J, Kurdistani Siavash K Epigenetic reprogramming by adenovirus e1a. Science (New York, N.Y.). 2008; 321(5892): 1086-8. Peng Weimin, Togawa Cynthia, Zhang Kangling, Kurdistani Siavash K Regulators of cellular levels of histone acetylation in Saccharomyces cerevisiae. Genetics. 2008; 179(1): 277-89. Pham Hung, Ferrari Roberto, Cokus Shawn J, Kurdistani Siavash K, Pellegrini Matteo Modeling the regulatory network of histone acetylation in Saccharomyces cerevisiae. Molecular systems biology. 2007; 3(1): 153. 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. 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. Kim KT, Ongusaha PP, Hong YK, Kurdistani SK, Nakamura M, Lu KP, Lee SW Function of Drg1/Rit42 in p53-dependent mitotic spindle checkpoint. The Journal of biological chemistry. . 2004; 279(37): 38597-602. Kurdistani SK, Tavazoie S, Grunstein M Mapping global histone acetylation patterns to gene expression. Cell. . 2004; 117(6): 721-33. 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. 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. 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. Reimer CL, Borras AM, Kurdistani SK, Garreau JR, Chung M, Aaronson SA, Lee SW Altered regulation of cyclin G in human breast cancer and its specific localization at replication foci in response to DNA damage in p53+/+ cells. The Journal of biological chemistry. . 1999; 274(16): 11022-9. Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer research. . 1998; 58(19): 4439-44.