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    Oliver J Rando MD, PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentBiochemistry and Molecular Pharmacology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-8879
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBioinformatics and Computational Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBioinformatics and Integrative Biology

        Overview 
        Narrative

        Oliver Rando

        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?



        Rotation Projects

        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.



        Post Docs

        For more information about the Postdoctoral position in Dr. Rando’s lab please use the link provided.
        Post doc position



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Yildirim O, Hung JH, Cedeno RJ, Weng Z, Lengner CJ, Rando OJ. A System for Genome-Wide Histone Variant Dynamics In ES Cells Reveals Dynamic MacroH2A2 Replacement at Promoters. PLoS Genet. 2014 Aug; 10(8):e1004515.
          View in: PubMed
        2. Carone BR, Hung JH, Hainer SJ, Chou MT, Carone DM, Weng Z, Fazzio TG, Rando OJ. High-resolution mapping of chromatin packaging in mouse embryonic stem cells and sperm. Dev Cell. 2014 Jul 14; 30(1):11-22.
          View in: PubMed
        3. Sharma U, Rando OJ. Father-Son Chats: Inheriting Stress through Sperm RNA. Cell Metab. 2014 Jun 3; 19(6):894-5.
          View in: PubMed
        4. Hughes AL, Rando OJ. Mechanisms underlying nucleosome positioning in vivo. Annu Rev Biophys. 2014 May 6; 43:41-63.
          View in: PubMed
        5. Soares LM, Radman-Livaja M, Lin SG, Rando OJ, Buratowski S. Feedback Control of Set1 Protein Levels Is Important for Proper H3K4 Methylation Patterns. Cell Rep. 2014 Mar 27; 6(6):961-72.
          View in: PubMed
        6. Watanabe S, Radman-Livaja M, Rando OJ, Peterson CL. A histone acetylation switch regulates H2A.Z deposition by the SWR-C remodeling enzyme. Science. 2013 Apr 12; 340(6129):195-9.
          View in: PubMed
        7. Möbius W, Osberg B, Tsankov AM, Rando OJ, Gerland U. Toward a unified physical model of nucleosome patterns flanking transcription start sites. Proc Natl Acad Sci U S A. 2013 Apr 2; 110(14):5719-24.
          View in: PubMed
        8. Chen HV, Rando OJ. Painting by numbers: increasing the parts list for chromatin domains. Mol Cell. 2013 Feb 21; 49(4):620-1.
          View in: PubMed
        9. Schug TT, Erlebacher A, Leibowitz S, Ma L, Muglia LJ, Rando OJ, Rogers JM, Romero R, vom Saal FS, Wise DL. Fetal programming and environmental exposures: implications for prenatal care and preterm birth. Ann N Y Acad Sci. 2012 Dec; 1276:37-46.
          View in: PubMed
        10. Rando OJ. Daddy issues: paternal effects on phenotype. Cell. 2012 Nov 9; 151(4):702-8.
          View in: PubMed
        11. Wang J, Zhuang J, Iyer S, Lin X, Whitfield TW, Greven MC, Pierce BG, Dong X, Kundaje A, Cheng Y, Rando OJ, Birney E, Myers RM, Noble WS, Snyder M, Weng Z. Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors. Genome Res. 2012 Sep; 22(9):1798-812.
          View in: PubMed
        12. Hughes AL, Jin Y, Rando OJ, Struhl K. A functional evolutionary approach to identify determinants of nucleosome positioning: a unifying model for establishing the genome-wide pattern. Mol Cell. 2012 Oct 12; 48(1):5-15.
          View in: PubMed
        13. Weiner A, Chen HV, Liu CL, Rahat A, Klien A, Soares L, Gudipati M, Pfeffner J, Regev A, Buratowski S, Pleiss JA, Friedman N, Rando OJ. Systematic dissection of roles for chromatin regulators in a yeast stress response. PLoS Biol. 2012; 10(7):e1001369.
          View in: PubMed
        14. Radman-Livaja M, Quan TK, Valenzuela L, Armstrong JA, van Welsem T, Kim T, Lee LJ, Buratowski S, van Leeuwen F, Rando OJ, Hartzog GA. A key role for Chd1 in histone H3 dynamics at the 3' ends of long genes in yeast. PLoS Genet. 2012; 8(7):e1002811.
          View in: PubMed
        15. Carone BR, Rando OJ. Rewriting the epigenome. Cell. 2012 Jun 22; 149(7):1422-3.
          View in: PubMed
        16. Fazzio TG, Rando OJ. NURDs are required for diversity. EMBO J. 2012 Jul 18; 31(14):3036-7.
          View in: PubMed
        17. Xu J, Yanagisawa Y, Tsankov AM, Hart C, Aoki K, Kommajosyula N, Steinmann KE, Bochicchio J, Russ C, Regev A, Rando OJ, Nusbaum C, Niki H, Milos P, Weng Z, Rhind N. Genome-wide identification and characterization of replication origins by deep sequencing. Genome Biol. 2012; 13(4):R27.
          View in: PubMed
        18. Rando OJ. Combinatorial complexity in chromatin structure and function: revisiting the histone code. Curr Opin Genet Dev. 2012 Apr; 22(2):148-55.
          View in: PubMed
        19. Rando OJ, Winston F. Chromatin and transcription in yeast. Genetics. 2012 Feb; 190(2):351-87.
          View in: PubMed
        20. Yildirim O, Li R, Hung JH, Chen PB, Dong X, Ee LS, Weng Z, Rando OJ, Fazzio TG. Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell. 2011 Dec 23; 147(7):1498-510.
          View in: PubMed
        21. Sikorski TW, Ficarro SB, Holik J, Kim T, Rando OJ, Marto JA, Buratowski S. Sub1 and RPA associate with RNA polymerase II at different stages of transcription. Mol Cell. 2011 Nov 4; 44(3):397-409.
          View in: PubMed
        22. Tsankov A, Yanagisawa Y, Rhind N, Regev A, Rando OJ. Evolutionary divergence of intrinsic and trans-regulated nucleosome positioning sequences reveals plastic rules for chromatin organization. Genome Res. 2011 Nov; 21(11):1851-62.
          View in: PubMed
        23. Radman-Livaja M, Verzijlbergen KF, Weiner A, van Welsem T, Friedman N, Rando OJ, van Leeuwen F. Patterns and mechanisms of ancestral histone protein inheritance in budding yeast. PLoS Biol. 2011 Jun; 9(6):e1001075.
          View in: PubMed
        24. Radman-Livaja M, Ruben G, Weiner A, Friedman N, Kamakaka R, Rando OJ. Dynamics of Sir3 spreading in budding yeast: secondary recruitment sites and euchromatic localization. EMBO J. 2011 Mar 16; 30(6):1012-26.
          View in: PubMed
        25. Papamichos-Chronakis M, Watanabe S, Rando OJ, Peterson CL. Global regulation of H2A.Z localization by the INO80 chromatin-remodeling enzyme is essential for genome integrity. Cell. 2011 Jan 21; 144(2):200-13.
          View in: PubMed
        26. Rando OJ. Genome-wide measurement of histone H3 replacement dynamics in yeast. Methods Mol Biol. 2011; 759:41-60.
          View in: PubMed
        27. Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Bock C, Li C, Gu H, Zamore PD, Meissner A, Weng Z, Hofmann HA, Friedman N, Rando OJ. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010 Dec 23; 143(7):1084-96.
          View in: PubMed
        28. Ivanovska I, Jacques PÉ, Rando OJ, Robert F, Winston F. Control of chromatin structure by spt6: different consequences in coding and regulatory regions. Mol Cell Biol. 2011 Feb; 31(3):531-41.
          View in: PubMed
        29. Lopes da Rosa J, Holik J, Green EM, Rando OJ, Kaufman PD. Overlapping regulation of CenH3 localization and histone H3 turnover by CAF-1 and HIR proteins in Saccharomyces cerevisiae. Genetics. 2011 Jan; 187(1):9-19.
          View in: PubMed
        30. Kim TS, Liu CL, Yassour M, Holik J, Friedman N, Buratowski S, Rando OJ. RNA polymerase mapping during stress responses reveals widespread nonproductive transcription in yeast. Genome Biol. 2010; 11(7):R75.
          View in: PubMed
        31. Tsankov AM, Thompson DA, Socha A, Regev A, Rando OJ. The role of nucleosome positioning in the evolution of gene regulation. PLoS Biol. 2010; 8(7):e1000414.
          View in: PubMed
        32. Jensen JD, Rando OJ. Recent evidence for pervasive adaptation targeting gene expression attributable to population size change. Proc Natl Acad Sci U S A. 2010 Jul 6; 107(27):E109-10; author reply 111.
          View in: PubMed
        33. Kaufman PD, Rando OJ. Chromatin as a potential carrier of heritable information. Curr Opin Cell Biol. 2010 Jun; 22(3):284-90.
          View in: PubMed
        34. Rando OJ. Genome-wide mapping of nucleosomes in yeast. Methods Enzymol. 2010; 470:105-18.
          View in: PubMed
        35. Radman-Livaja M, Liu CL, Friedman N, Schreiber SL, Rando OJ. Replication and active demethylation represent partially overlapping mechanisms for erasure of H3K4me3 in budding yeast. PLoS Genet. 2010 Feb; 6(2):e1000837.
          View in: PubMed
        36. Hughes A, Rando OJ. Chromatin 'programming' by sequence--is there more to the nucleosome code than %GC? J Biol. 2009; 8(11):96.
          View in: PubMed
        37. Weiner A, Hughes A, Yassour M, Rando OJ, Friedman N. High-resolution nucleosome mapping reveals transcription-dependent promoter packaging. Genome Res. 2010 Jan; 20(1):90-100.
          View in: PubMed
        38. Rowat AC, Bird JC, Agresti JJ, Rando OJ, Weitz DA. Tracking lineages of single cells in lines using a microfluidic device. Proc Natl Acad Sci U S A. 2009 Oct 27; 106(43):18149-54.
          View in: PubMed
        39. Radman-Livaja M, Rando OJ. Nucleosome positioning: how is it established, and why does it matter? Dev Biol. 2010 Mar 15; 339(2):258-66.
          View in: PubMed
        40. Rando OJ, Chang HY. Genome-wide views of chromatin structure. Annu Rev Biochem. 2009; 78:245-71.
          View in: PubMed
        41. Rando OJ. Evolution in a test tube: the hatchet before the scalpel. Cell. 2008 Nov 28; 135(5):789-91.
          View in: PubMed
        42. Kaplan T, Liu CL, Erkmann JA, Holik J, Grunstein M, Kaufman PD, Friedman N, Rando OJ. Cell cycle- and chaperone-mediated regulation of H3K56ac incorporation in yeast. PLoS Genet. 2008 Nov; 4(11):e1000270.
          View in: PubMed
        43. Chechik G, Oh E, Rando O, Weissman J, Regev A, Koller D. Activity motifs reveal principles of timing in transcriptional control of the yeast metabolic network. Nat Biotechnol. 2008 Nov; 26(11):1251-9.
          View in: PubMed
        44. Jeddeloh JA, Greally JM, Rando OJ. Reduced-representation methylation mapping. Genome Biol. 2008; 9(8):231.
          View in: PubMed
        45. Rando O. A biologist despairs over the difficulty of demonstrating heritability of chromatin states. Nature. 2008 Jul 10; 454(7201):141.
          View in: PubMed
        46. Au WC, Crisp MJ, DeLuca SZ, Rando OJ, Basrai MA. Altered dosage and mislocalization of histone H3 and Cse4p lead to chromosome loss in Saccharomyces cerevisiae. Genetics. 2008 May; 179(1):263-75.
          View in: PubMed
        47. Whitehouse I, Rando OJ, Delrow J, Tsukiyama T. Chromatin remodelling at promoters suppresses antisense transcription. Nature. 2007 Dec 13; 450(7172):1031-5.
          View in: PubMed
        48. Rando O. Oliver Rando: taking chromatin analysis to the genomic scale. Interview by Ruth Williams. J Cell Biol. 2007 Jun 18; 177(6):948-9.
          View in: PubMed
        49. Dennis JH, Fan HY, Reynolds SM, Yuan G, Meldrim JC, Richter DJ, Peterson DG, Rando OJ, Noble WS, Kingston RE. Independent and complementary methods for large-scale structural analysis of mammalian chromatin. Genome Res. 2007 Jun; 17(6):928-39.
          View in: PubMed
        50. Rando OJ, Ahmad K. Rules and regulation in the primary structure of chromatin. Curr Opin Cell Biol. 2007 Jun; 19(3):250-6.
          View in: PubMed
        51. Dion MF, Kaplan T, Kim M, Buratowski S, Friedman N, Rando OJ. Dynamics of replication-independent histone turnover in budding yeast. Science. 2007 Mar 9; 315(5817):1405-8.
          View in: PubMed
        52. Rando OJ, Verstrepen KJ. Timescales of genetic and epigenetic inheritance. Cell. 2007 Feb 23; 128(4):655-68.
          View in: PubMed
        53. Rando OJ. Global patterns of histone modifications. Curr Opin Genet Dev. 2007 Apr; 17(2):94-9.
          View in: PubMed
        54. Rando OJ. Chromatin structure in the genomics era. Trends Genet. 2007 Feb; 23(2):67-73.
          View in: PubMed
        55. Kim M, Vasiljeva L, Rando OJ, Zhelkovsky A, Moore C, Buratowski S. Distinct pathways for snoRNA and mRNA termination. Mol Cell. 2006 Dec 8; 24(5):723-34.
          View in: PubMed
        56. Rando OJ, Paulsson J. Noisy silencing of chromatin. Dev Cell. 2006 Aug; 11(2):134-6.
          View in: PubMed
        57. Raisner RM, Hartley PD, Meneghini MD, Bao MZ, Liu CL, Schreiber SL, Rando OJ, Madhani HD. Histone variant H2A.Z marks the 5' ends of both active and inactive genes in euchromatin. Cell. 2005 Oct 21; 123(2):233-48.
          View in: PubMed
        58. Liu CL, Kaplan T, Kim M, Buratowski S, Schreiber SL, Friedman N, Rando OJ. Single-nucleosome mapping of histone modifications in S. cerevisiae. PLoS Biol. 2005 Oct; 3(10):e328.
          View in: PubMed
        59. Yuan GC, Liu YJ, Dion MF, Slack MD, Wu LF, Altschuler SJ, Rando OJ. Genome-scale identification of nucleosome positions in S. cerevisiae. Science. 2005 Jul 22; 309(5734):626-30.
          View in: PubMed
        60. Casolari JM, Brown CR, Drubin DA, Rando OJ, Silver PA. Developmentally induced changes in transcriptional program alter spatial organization across chromosomes. Genes Dev. 2005 May 15; 19(10):1188-98.
          View in: PubMed
        61. Dion MF, Altschuler SJ, Wu LF, Rando OJ. Genomic characterization reveals a simple histone H4 acetylation code. Proc Natl Acad Sci U S A. 2005 Apr 12; 102(15):5501-6.
          View in: PubMed
        62. Kim M, Krogan NJ, Vasiljeva L, Rando OJ, Nedea E, Greenblatt JF, Buratowski S. The yeast Rat1 exonuclease promotes transcription termination by RNA polymerase II. Nature. 2004 Nov 25; 432(7016):517-22.
          View in: PubMed
        63. Rando OJ, Chi TH, Crabtree GR. Second messenger control of chromatin remodeling. Nat Struct Biol. 2003 Feb; 10(2):81-3.
          View in: PubMed
        64. Diehn M, Alizadeh AA, Rando OJ, Liu CL, Stankunas K, Botstein D, Crabtree GR, Brown PO. Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc Natl Acad Sci U S A. 2002 Sep 3; 99(18):11796-801.
          View in: PubMed
        65. Rando OJ, Zhao K, Janmey P, Crabtree GR. Phosphatidylinositol-dependent actin filament binding by the SWI/SNF-like BAF chromatin remodeling complex. Proc Natl Acad Sci U S A. 2002 Mar 5; 99(5):2824-9.
          View in: PubMed
        66. Rando OJ, Zhao K, Crabtree GR. Searching for a function for nuclear actin. Trends Cell Biol. 2000 Mar; 10(3):92-7.
          View in: PubMed
        67. Zhao K, Wang W, Rando OJ, Xue Y, Swiderek K, Kuo A, Crabtree GR. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell. 1998 Nov 25; 95(5):625-36.
          View in: PubMed
        68. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9; 78(5):773-85.
          View in: PubMed
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