Postdoctoral Position Available

Oliver J. Rando, Ph.D.,M.D.

Academic Role: Assistant Professor

Faculty Appointment(s) In:
   Biochemistry and Molecular Pharmacology

Genomic approaches to chromatin structure and function, and to epigenetic inheritance.

Public data sets:
http://users.umassmed.edu/Oliver.Rando/

Organisms sharing identical genomes may nonetheless exhibit heritable variation in traits that are now called “epigenetic” traits. Information carriers for epigenetic traits include prion conformation and cytosine methylation, and it is widely believed that the packaging of eukaryotic genomes into chromatin provides another carrier of epigenetic information. Epigenetics is of great interest for researchers interested in fields ranging from systems biology to evolution to human disease.

Our lab is broadly interested in epigenetic inheritance, but most of our research focuses on one putative carrier of epigenetic information – the nucleoprotein complex known as chromatin. We utilize “genomics” tools such as DNA microarrays and high-throughput sequencing to measure chromatin structure over entire genomes at single-nucleosome resolution, with the eventual goal of determining how chromatin states are established and maintained.

We consider the primary sequence of chromatin to consist of three major features – the positioning of nucleosomes relative to underlying genomic sequence, the covalent modification pattern of each nucleosome, and the histone variants comprising each histone octamer. To date, we have measured these three features in actively growing yeast cultures, and have also measured the exchange rates of histone H3 in G1-arrested yeast. A number of interesting features emerge from these studies:

Most interesting, we have identified what may be considered “motifs” in chromatin structure in yeast. For example, yeast promoters are characterized by a nucleosome-free region (NFR) of about 140 bp flanked by two well-positioned nucleosomes that lack a number of modifications such as H4K16ac, and that are rapidly replaced throughout the cell cycle. The +1 nucleosome also tends to carry Htz1 in place of H2A, while the -1 nucleosome carries Htz1 at a subset of promoters.

Another interesting feature of yeast chromatin is that covalent modifications tend to occur in a small number of highly-correlated groups, suggesting that histone modification patterns do not encode complex “messages.”  Nonetheless, the abundance of covalent modifications (over 100 have been described!!!) raises the question of why so many exist.

By measuring histone replacement dynamics, we have found that coding regions are surprisingly “cold”, meaning the passage of RNA polymerase does not result in nucleosome replacement except at extremely high transcription rates. Heterochromatin is also cold, while promoter and tRNA genes are associated with hot nucleosomes. Chromatin boundaries – sequences whose presence prevents the lateral spread of silencing complexes from a nucleating element – are also associated with rapidly-exchanged nucleosomes, suggesting that “scrubbing” or chromatin by rapid replacement serves as the mechanism to limit this lateral spreading.

Our lab is interested in the following questions:

1) What are the rules by which chromatin motifs are generated? How do genomic sequences, and factors such as RNA polymerase passage, result in the common chromatin patterns seen at so many genes?

2) What are the mechanisms resulting in replication-independent histone replacement?

3) What are there so many histone modifications? What are the “systems” features that result from histone modification crosstalk?

4) More generally, how does chromatin act as a signal filter in cells, given its location between upstream signaling pathways and downstream transcriptional outcomes?

5) What happens to nucleosomes during genomic replication, and how do old nucleosomes influence the states of newly-incorporated nucleosomes? What is the machinery required to maintain a chromatin state?

6) How does chromatin structure change over evolution, and how do chromatin regulators contribute to phenotypic divergence in closely-related species?

7) What phenotypes are epigenetically heritable, and under what conditions is a selective advantage conferred by stochastic switching as opposed to plastic responsiveness to the environment?

8) How is the genome packaged in sperm and embryonic stem cells, and how do histone dynamics change during differentiation?

Publications

Research

Dennis, J.H., Fan, H.Y., Reynolds, S.M., Yuan, G., Meldrim, J.C., Richter, D.J., Peterson, D.G., Rando, O.J., Noble, W.S., Kingston, R.E.  “Independent and complementary methods for large-scale structural analysis of mammalian chromatin”, Genome Res 2007, 17, 928-39.

Dion, M.F., Kaplan, T., Kim, M., Buratowski, S., Friedman, N., Rando, O.J.   “Dynamics of replication-independent histone turnover in budding yeast”, Science 2007, 315, 1405-8.

Kim, M., Vasiljeva, L., Rando, O.J., Zhelkovsky, A., Moore, C., Buratowski, S. “Distinct pathways for snoRNA and mRNA termination”, Mol Cell 2006, 24, 723-34.

Raisner, R.M., Hartley, P.D., Meneghini, M.D., Bao, M.Z., Liu, C.L., Schreiber, S.L., Rando, O.J., Madhani, H.D.  “Histone variant H2A.Z marks the 5’ ends of both active and inactive genes in euchromatin”, Cell 2005, 123: 233-48

Liu, C.L., Kaplan, T., Kim, M., Buratowski, S., Schreiber, S.L., Friedman, N., Rando, O.J.  “Single-nucleosome mapping of histone modifications in S. cerevisiae”, PLoS Biology 2005, 3: e328.

Yuan, G.C., Liu, Y.J., Dion, M.F., Slack, M.D., Wu, L.F., Altschuler, S.J., Rando, O.J.  “Genome-scale identification of nucleosome positions in S. cerevisiae”, Science 2005, 309: 626-30.

Casolari, J.M., Brown, C.R., Drubin, D.A., Rando, O.J., Silver, P.A.  “Developmentally induced changes in transcriptional program alter spatial organization across chromosomes”, Genes Dev 2005, 19: 1188-98.

Dion, M.F., Altschuler, S.J., Wu, L.F., Rando, O.J.  “Genomic characterization reveals a simple histone H4 acetylation code”, PNAS 2005, 102: 5501-06.

Kim, M., Krogan, N.J., Vasiljeva, L., Rando, O.J., Nedea, E., Greenblatt, J.F., Buratowski, S.  “The yeast Rat1 exonuclease promotes transcription termination by RNA polymerase II”, Nature 2004, 432: 517-22.

Diehn, M.*, Alizadeh, A.A.*, Rando, O.J.*, Liu, C.L.*, Stankunas, K., Botstein, D., Crabtree, G.R., Brown, P.O.  “Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation”, PNAS 2002, 99: 11796-801.  * Indicates authors contributing equally.

Rando, O.J., Zhao, K., Janmey, P., Crabtree, G.R.   “Phosphatidylinositol-dependent actin filament binding by the SWI/SNF-like BAF chromatin remodeling complex”, PNAS 2002, 99: 2824-9.

Zhao, K., Wang, W., Rando, O.J., Xue, Y., Swiderek, K., Kuo, A., Crabtree, G.R.  “Rapid and   phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling”, Cell 1998, 95: 625-36.

Palombella, V.J., Rando, O.J., Goldberg, A.L., Maniatis, T.  “The ubiquitin-proteasome system is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B”, Cell 1994, 78: 773-85.

Reviews

Rando, O.J., Ahmad, K.   “Rules and regulation in the primary structure of chromatin”, Curr Opin Cell Biol 2007, 19, 250-6.

Rando, O.J., Verstrepen, K.J.   “Time scales of genetic and epigenetic inheritance”, Cell 2007, 128, 655-68.

Rando, O.J.   “Global patterns of histone modifications”, Curr Opin Genet Dev 2007, 17, 94-9.

Rando, O.J.   “Chromatin structure in the genomic era”, Trends Genet 2007, 23, 67-73.

Rando, O.J., Paulsson, J.   “Noisy silencing of chromatin”, Dev Cell 2006, 11: 134-6

Rando, O.J., Chi, T., Crabtree, G.R.   “Second messenger control of chromatin remodeling”, Nat Struct Biol 2003, 10: 81-3

Rando, O.J., Zhao, K., Crabtree, G.R.   “Searching for a function for nuclear actin”, Trends Cell Biol. 2000, 10: 92-97.

Rotation projects are available to study chromatin structure and function.

Project 1. Measure histone dynamics in yeast.

Histone dynamics play major roles in chromatin metabolism and in the inheritance of chromatin states. To measure histone replacement rates in yeast, we have created yeast strains carrying inducible epitope-tagged histones H3 and H2A. Using microarrays, we will measure histone replacement rates in a variety of mutant yeast to ascertain the role of various chromatin remodeling factors in histone exchange reactions.

Project 2. Characterize mechanisms for epigenetic inheritance in yeast.

We have identified a variety of genes whose expression state in yeast is epigenetically heritable. We will screen the yeast genome for genes that affect the inheritance of these expression patterns.

Project 3. Measure histone dynamics in embryonic stem cells.

Embryonic stem cells are pluripotent cells that can give rise to every type of cell in the adult animal. The role of chromatin structure in maintaining this pluripotent state is poorly understood, but it appears that stem cell chromatin is exceptionally labile relative to that in differentiated cells. We will create stem cell lines with inducible tagged histones to measure histone replacement rates across the mouse genome.

Office: LRB 903
Phone: 508-856-8879
E-mail: Oliver.Rando@umassmed.edu
Keywords: Stem Cell Biology, Chromosome Structure & Dynamics, Systems Biology, Gene Expression, Genomics

More on Oliver J. Rando's Research Research | Publications | Rotations View All Sections on One Page

Postdoctoral Position Available A postdoctoral position is available to study in this laboratory. Contact Dr. Rando for additional details.