Harvard University - Department of Molecular & Cellular Biology

MEMBERS OF THE BOARD OF TUTORS

Leschziner, Andres, Ph.D.

Department of Molecular and Cellular Biology, Harvard University

http://www.mcb.harvard.edu/Leschziner/

profile_image Structural biology of ATP-dependent chromatin remodeling


The extreme degree of compaction of DNA into chromatin would seem to create an insurmountable barrier to all DNA transactions. However, a variety of mechanisms have evolved that allow cells to turn this apparent impediment into a highly dynamic and finely tuned regulatory device that controls the accessibility of specific DNA sequences. A multitude of players are involved in achieving this regulation. A number of protein factors are involved in covalently modifying chromatin--either DNA itself or the histone octamer around which DNA is wrapped. Another group, the ATP-dependent chromatin remodeling complexes, utilizes the energy from ATP hydrolysis to non-covalently modify nucleosomes. These remodelers are large (often above 1 MDa) multi-subunit complexes that are conserved from yeast to humans and their activity leads to a number of different fates for the remodeled nucleosomes: sliding along DNA, transfer to a different DNA segment, formation of a "loose" nucleosome structure and exchange of histone components. Despite a significant body of work describing these outcomes we do not yet understand mechanistically how ATP-dependent chromatin remodelers actually remodel chromatin.


Our group is approaching this question from a structural point of view. We use primarily three-dimensional electron microscopy (3D EM) to study the ATP-dependent chromatin remodeling complex RSC (Remodels the Structure of Chromatin) from S.cerevisiae. This complex has been extensively characterized biochemically and genetically, making it an ideal model system. Electron microscopy is a powerful structural technique to study large macromolecular assemblies that are not amenable to more traditional methods either due to their low abundance (when purified from natural sources, for example) or refractory to crystallization (due to their intrinsic flexibility). More importantly, electron microscopy of vitrified samples (cryo-EM) holds the promise of allowing us to image--at high resolution and under physiological conditions--the conformational diversity present in and potentially central to the function of many macromolecular assemblies.


The long-term goal of our research is to visualize the entire remodeling mechanism at high resolution in order to understand its chemical underpinnings. In the meantime, we are starting to dissect RSC at lower resolution. We have obtained an initial reconstruction of the complex and are in the process of obtaining one of RSC bound to its substrate, the nucleosome. At the same time, we will build a map of the positions of a number of the 15 different subunits that comprise RSC by tagging them and probing their location; this will help us better understand their biological role within the complex. The group is also interested in what remains one of the major challenges in 3D EM--obtaining initial models of novel samples. We recently developed a new reconstruction method (Orthogonal Tilt Reconstruction) that addresses some of the problems and limitations of existing approaches. We are interested in further developing this method and eventually automating it to make the generation of initial models a robust and routine aspect of 3D EM.

next tutor: Liberles, Stephen

Below is a listing of current tutors:

  • (1)   Aldovini, Anna , M.D., Division of Infectious Diseases, Children's Hospital
  • (2)   Auld, David , Ph.D., Department of Biology, Boston College
  • (3)   Ausubel, Frederick , Ph.D., Department of Molecular Biology, Massachusetts General Hospital
  • (4)   Berg, Howard , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (5)   Brenner, Michael , Ph.D., Division of Engineering and Applied Sciences, Harvard University
  • (6)   Brenner, Tamara , Ph.D., Life Sciences Division, Harvard University
  • (7)   Buratowski, Stephen , Ph.D., BCMP, Harvard Medical School
  • (8)   Burton, Briana , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (9)   Carroll, Michael , Ph.D., CBR Institute for Biomedical Research, Harvard Medical School
  • (10)   Chen, Bing , Ph.D., Laboratory of Molecular Medicine, Children's Hospital
  • (11)   Chou, James , Ph.D., BCMP, Harvard Medical School
  • (12)   Clapham, David , M.D., Ph.D., Department of Neurobiology, Children's Hospital
  • (13)   Clardy, John , Ph.D., BCMP, Harvard Medical School
  • (14)   D'Souza, Victoria , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (15)   DePace, Angela , Ph.D., Department of Systems Biology, Harvard Medical School
  • (16)   Dulac, Catherine , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (17)   Eck, Michael , M.D., Ph.D., BCMP, Dana-Farber Cancer Institute
  • (18)   Eggan, Kevin , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (19)   Engert, Florian , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (20)   Erikson, Raymond , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (21)   Fisher, David , M.D., Ph.D., Department of Pediatrics, Dana Farber Cancer Institute
  • (22)   Fraenkel, Dan , Ph.D., Microbiology and Molecular Genetics, Harvard Medical School
  • (23)   Fraenkel, Ernest , Ph.D., Division of Biological Engineering, Massachusetts Institute of Technology
  • (24)   Fraenkel, Paula , M.D., Hematology/Oncology, Beth Israel Deaconess Medical Center
  • (25)   Gaudet, Rachelle , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (26)   Goldfeld, Anne , M.D., CBR Institute for Biomedical Research, Harvard Medical School
  • (27)   Goldstein, Richard , Ph.D., Professor of Pediatrics, Boston Medical Center
  • (28)   Gray, Nathanael , Ph.D., BCMP, Harvard Medical School
  • (29)   Guidotti, Guido , M.D., Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (30)   Haigis, Marcia , Ph.D., Department of Pathology, Harvard Medical School
  • (31)   Harrison, Stephen , Ph.D., BCMP, Harvard Medical School
  • (32)   Hedley, Mary Lynne , Ph.D., MGI Pharma Biologics
  • (33)   Hinds, Philip , Ph.D., Molecular Oncology Research Institute, Tufts - New England Medical Center
  • (34)   Hung, Deborah , M.D., Ph.D., Microbiology and Molecular Genetics, Harvard Medical School
  • (35)   Hunter, Craig , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (36)   Jasanoff, Alan , Ph.D., Nuclear Engineering/Brain & Cognitive Sciences, Massachusetts Institute of Technology
  • (37)   Kahne, Daniel , Ph.D., Department of Chemistry and Chemical Biology, Harvard University
  • (38)   Kay, Jeremy , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (39)   Kieff, Elliott , M.D., Ph.D., Channing Laboratory, Brigham and Women's Hospital
  • (40)   Kirchhausen, Tomas , Ph.D., CBR Institute for Biomedical Research, Harvard Medical School
  • (41)   Kishony, Roy , Ph.D., Department of Systems Biology, Harvard Medical School
  • (42)   Kleckner, Nancy , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (43)   Kolter, Roberto , Ph.D., Microbiology and Molecular Genetics, Harvard Medical School
  • (44)   Kopcow, Hernan , Ph.D., Department of Medicine, Beth Israel Deaconess Medical Center
  • (45)   Kunes, Samuel , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (46)   Lahav, Galit , Ph.D., Department of Systems Biology, Harvard Medical School
  • (47)   Leschziner, Andres , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (48)   Liberles, Stephen , Ph.D., Department of Cell Biology, Harvard Medical School
  • (49)   Lichtman, Jeff , M.D., Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (50)   Lieberman, Judy , M.D., Ph.D., CBR Institute for Biomedical Research, Harvard Medical School
  • (51)   Lilley, Brendan , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (52)   Livingston, David , M.D., Department of Genetics, Dana-Farber Cancer Institute
  • (53)   Loeken, Mary , Ph.D., Developmental and Stem Cell Biology, Joslin Diabetes Center, Harvard Medical School
  • (54)   Losick, Richard , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (55)   Lue, Robert , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (56)   Magasanik, Boris , Ph.D., Biology Department, Massachusetts Institute of Technology
  • (57)   McKeon, Frank , Ph.D., Department of Cell Biology, Harvard Medical School
  • (58)   Michel, Thomas , M.D., Ph.D., Cardiovascular Division, Brigham and Women's Hospital
  • (59)   Miller, Jeffrey , Ph.D., Neuromuscular Biology & Disease Group, Boston Biomedical Research Institute
  • (60)   Miller, Theodore , Ph.D., Chief Executive Officer, Reify Corporation
  • (61)   Moazed, Danesh , Ph.D., Department of Cell Biology, Harvard Medical School
  • (62)   Murthy, Venkatesh , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (63)   Navia, Manuel , , Oxford Bioscience Partners
  • (64)   Nelson, David , Ph.D., Department of Physics, Harvard University
  • (65)   Olesen, James , Ph.D., Wilmer Cutler Pickering Hale and Door LLP
  • (66)   Peattie, Debra , MBA, Ph.D., Harvard University
  • (67)   Ranjbar, Shahin , Ph.D., Children's Hospital, Harvard Medical School
  • (68)   Rheinwald, James , Ph.D., Department of Dermatology, Brigham and Women's Hospital
  • (69)   Rivera-Feliciano, Jose , Ph.D., Stem Cell and Regenerative Biology, Harvard University
  • (70)   Sabeti, Pardis , D.Phil, M.D., FAS Center for Systems Biology, Harvard University
  • (71)   Sanes, Joshua , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (72)   Sassanfar, Mandana , Ph.D., Department of Biology, Massachusetts Institute of Technology
  • (73)   Sato, Vicki , Ph.D., Technology and Operations Management, Harvard Business School
  • (74)   Schier, Alexander , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (75)   Shamu, Caroline , Ph.D., Department of Systems Biology, Harvard Medical School
  • (76)   Shi, Yang , Ph.D., Department of Pathology, Harvard Medical School
  • (77)   Silberstein, Lev , M.D., Ph.D., Harvard University
  • (78)   Starnbach, Michael , Ph.D., Microbiology and Molecular Genetics, Harvard Medical School
  • (79)   Stern, Bodo , Ph.D., FAS Center for Systems Biology, Harvard University
  • (80)   Stern, Joel N.H. , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (81)   Strominger, Jack , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (82)   Sweadner, Kathleen , M.D., Harvard University
  • (83)   Tong, Jeffrey , Ph.D., Nora Therapeutics
  • (84)   Torello, A. Thomas , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (85)   Toth, Joseph , Ph.D., Merrimack Pharmaceuticals
  • (86)   Tucci, Greg , Ph.D., Department of Chemistry and Chemical Biology, Harvard University
  • (87)   Vaughan, Cheryl , Ph.D., Graduate Program in Biotechnology, Harvard University
  • (88)   Viel, Alain , Ph.D., Department of Molecular and Cellular Biology, Harvard University
  • (89)   Walker, Suzanne , Ph.D., Microbiology and Molecular Genetics, Harvard Medical School
  • (90)   Winston, Fred , Ph.D., Department of Genetics, Harvard Medical School