核小體(Nucleosome)是由去氧核醣核酸(DNA)序列纏繞4對組織蛋白(Histone)所組成，為構成真核生物染色質(Chromatin)的基本單位。核小體在基因區域的定位及組織蛋白上的後轉錄修飾(Post-translational modification)已被廣泛地研究，且多篇文獻均提出其結構的改變將會影響細胞的轉錄(Transcription)行為。近期，許多研究酵母菌染色質的團隊發表了多項全基因組染色質結構調控的實驗數據。這些DNA序列型式的實驗資料對往後的研究具有極大的參考價值，整合這些實驗數據將有利於分子生物學家對染色質調控及轉錄行為的研究。然而這些珍貴的實驗數據均分散在各篇文獻，且目前並無工具平台能夠有效地觀測這些關於染色質調控的資訊。因此，我們開發了YNA (Yeast Nucleosome Atlas)資料庫以整合目前大部分研究染色質調控的實驗數據。在YNA中，我們收集了多種類型的資料，其中包含了核小體定位資訊、組織蛋白後轉錄修飾，調控蛋白結合DNA序列位置，基因表現及基因功能類別等全基因組的資料。另外，我們開發了全基因組探勘功能(Genome-wide gene miner)，讓使用者能夠指定特定組合的染色質調控特徵做為過濾標準，以取得符合條件的基因列表，進而達到全基因組觀測的目的。除此之外，我們還實現了生物特性顯著分析功能(Biological significance analyzer)，在使用者取得基因列表後，針對多項此列表共有的特徵進行顯著性分析。此分析不但提供基因列表的特性趨勢做為參考，還對其他相關的調控機制提出可測試性的假說。相較於其他已發表的平台，YNA不但整合了多種染色質調控資訊，且最重要的是，YNA提供了搜尋及分析功能讓使用者能夠更深入觀測染色質調控及基因轉錄的相關性。這些都將有利生物學家進行往後更深入的研究。YNA目前已上線 http://cosbi2.ee.ncku.edu.tw/yna/。

The eukaryotic genome is packaged into nucleosomes, which comprise histone octamers wrapped by DNA segments. Nucleosome organization and histone modification have great influence on transcriptional regulations. Several evidences have suggested that different alterations on chromatin structure can cause distinct cellular events. Therefore, integration of these datasets can greatly assist the genome-wide investigation. However, most of these chromatin-related data are scattering in several literatures. And no comprehensive investigation tool on these data is available. To decipher the mechanism underlying transcription, we developed the Yeast Nucleosome Atlas database, or the YNA database, to integrate experimental data of nucleosome occupancy, histone modifications, factors for chromatin regulation, and expression profiles. In addition, to acquire experimentally testable hypotheses, we implemented the genome-wide gene miner to provide the interface for researchers to fetch gene lists by custom-defined filtering criteria based on those deposited datasets. Moreover, the biological significance analyzer, which analyzes the enrichment of coherent features from multiple aspects, was constructed to help researchers propose testable hypotheses for downstream analysis. Compared to those previously established genome browsing databases, YNA integrates comprehensive information about global chromatin structure and gene regulation. Most importantly, YNA provides gene mining and analyzing functions for advanced analysis. YNA is available online at http://cosbi2.ee.ncku.edu.tw/yna/.

[1] I. Albert, T. N.Mavrich, L. P. Tomsho, J. Qi, S. J. Zanton, S. C. Schuster, and B. F. Pugh, "Translational and rotational settings of H2A. Z nucleosomes across the Saccharomyces cerevisiae genome," Nature, vol. 446, no. 7135, pp. 572–576, 2007.
[2] R. Balakrishnan, J. Park, K. Karra, B. C. Hitz, G. Binkley, E. L. Hong, J. Sullivan, G. Micklem, and J. M. Cherry, "YeastMine—an integrated data warehouse for Saccharomyces cerevisiae data as a multipurpose tool-kit," Database: the journal of biological databases and curation, vol. 2012, Article ID bar062, doi:10.1093/database/bar062, 2012.
[3] H. Boeger, J. Griesenbeck, and R. D. Kornberg, "Nucleosome retention and the stochastic nature of promoter chromatin remodeling for transcription," Cell, vol. 133, no. 4, pp. 716–726, 2008.
[4] E. T. Chan and J. M. Cherry, "Considerations for creating and annotating the budding yeast Genome Map at SGD: a progress report," Database: the journal of biological databases and curation, vol. 2012, Article ID bar057, doi:10.1093/database/bar057, 2012.
[5] J.M. Cherry, C. Adler, C. Ball, S. A. Chervitz, S. S. Dwight, E. T. Hester, Y. Jia, G. Juvik, T. Roe, M. Schroeder, et al., "SGD: Saccharomyces genome database," Nucleic Acids Research, vol. 26, no. 1, pp. 73–79, 1998.
[6] J. M. Cherry, E. L. Hong, C. Amundsen, R. Balakrishnan, G. Binkley, E. T. Chan, K. R. Christie, M. C. Costanzo, S. S. Dwight, S. R. Engel, et al., "Saccharomyces Genome Database: the genomics resource of budding yeast," Nucleic Acids Research, vol. 40, no. D1, pp. D700–D705, 2012.
[7] W. L. Cheung, S. D. Briggs, and C. D. Allis, "Acetylation and chromosomal functions," Current Opinion in Cell Biology, vol. 12, no. 3, pp. 326–333, 2000.
[8] C. R. Clapier and B. R. Cairns, "The biology of chromatin remodeling complexes," Annual Review of Biochemistry, vol. 78, pp. 273–304, 2009.
[9] J. L. DeRisi, V. R. Iyer, and P. O. Brown, "Exploring the metabolic and genetic control of gene expression on a genomic scale," Science, vol. 278, no. 5338, pp. 680–686, 1997.
[10] T. G. Fazzio and T. Tsukiyama, "Chromatin remodeling in vivo: evidence for a nucleosome sliding mechanism," Molecular Cell, vol. 12, no. 5, pp. 1333–1340, 2003.
[11] Q. Feng, H. Wang, H. H. Ng, H. Erdjument-Bromage, P. Tempst, K. Struhl, and Y. Zhang, "Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain," Current Biology, vol. 12, no. 12, pp. 1052–1058, 2002.
[12] Y. Field, N. Kaplan, Y. Fondufe-Mittendorf, I. K. Moore, E. Sharon, Y. Lubling, J.Widom, and E. Segal, "Distinctmodes of regulation by chromatin encoded through nucleosome positioning signals," PLoS Computational Biology, vol. 4, no. 11, p. e1000216, 2008.
[13] B. Guillemette, A. R. Bataille, N. G´evry, M. Adam, M. Blanchette, F. Robert, and L. Gaudreau, "Variant histone H2A. Z is globally localized to the promoters of inactive yeast genes and regulates nucleosome positioning," PLoS Biology, vol. 3, no. 12, p. e384, 2005.
[14] B. Guillemette, P. Drogaris, H.-H. S. Lin, H. Armstrong, K. Hiragami-Hamada, A. Imhof, E. Bonneil, P. Thibault, A. Verreault, and R. J. Festenstein, "H3 lysine 4 is acetylated at active gene promoters and is regulated by H3 lysine 4 methylation," PLoS Genetics, vol. 7, no. 3, p. e1001354, 2011.
[15] P. D. Hartley and H. D. Madhani, "Mechanisms that specify promoter nucleosome location and identity," Cell, vol. 137, no. 3, pp. 445–458, 2009.
[16] W. J. L. T. H. C. G. M. G. T. L. E. Y. R. Holstege FC, Jennings EG, "Dissecting the regulatory circuitry of a eukaryotic genome," Cell, vol. 95, pp. 717–728, 1998.
[17] D. Hwang, A. G. Rust, S. Ramsey, J. J. Smith, D.M. Leslie, A. D.Weston, P. De Atauri, J. D. Aitchison, L. Hood, A. F. Siegel, et al., "A data integration methodology for systems biology," Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 48, pp. 17296–17301, 2005.
[18] D. Hwang, J. J. Smith, D.M. Leslie, A. D.Weston, A. G. Rust, S. Ramsey, P. de Atauri, A. F. Siegel, H. Bolouri, J. D. Aitchison, et al., "A data integration methodology for systems biology: experimental verification," Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 48, pp. 17302–17307, 2005.
[19] T. Ideker, T. Galitski, and L. Hood, "A new approach to decoding life: systems biology," Annual Review of Biochemistry, vol. 2, no. 1, pp. 343–372, 2001.
[20] N. Kaplan, I. K. Moore, Y. Fondufe-Mittendorf, A. J. Gossett, D. Tillo, Y. Field, E. M. LeProust, T. R. Hughes, J. D. Lieb, J. Widom, et al., "The DNA-encoded nucleosome organization of a eukaryotic genome," Nature, vol. 458, no. 7236, pp. 362–366, 2009.
[21] A. Kirmizis, H. Santos-Rosa, C. J. Penkett, M. A. Singer, M. Vermeulen, M. Mann, J. B¨ahler, R. D. Green, and T. Kouzarides, "Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation," Nature, vol. 449, no. 7164, pp. 928–932, 2007.
[22] R. D. Kornberg and Y. Lorch, "Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome," Cell, vol. 98, no. 3, pp. 285–294, 1999.
[23] E. Koutelou, C. L. Hirsch, and S. Y. Dent, "Multiple faces of the SAGA complex," Current Opinion in Cell Biology, vol. 22, no. 3, pp. 374–382, 2010.
[24] T. Kouzarides, "Chromatin modifications and their function," Cell, vol. 128, no. 4, pp. 693–705, 2007.
[25] J.-S. Lee, A. Shukla, J. Schneider, S. K. Swanson, M. P. Washburn, L. Florens, S. R. Bhaumik, and A. Shilatifard, "Histone crosstalk between H2B monoubiquitination and H3 methylation mediated by COMPASS," Cell, vol. 131, no. 6, pp. 1084–1096, 2007.
[26] S.-I. Lee, D. Pe’Er, A. M. Dudley, G. M. Church, and D. Koller, "Identifying regulatory mechanisms using individual variation reveals key role for chromatin modification," Proceedings of the National Academy of Sciences, vol. 103, no. 38, pp. 14062–14067, 2006.
[27] W. Lee, D. Tillo, N. Bray, R. H. Morse, R. W. Davis, T. R. Hughes, and C. Nislow, "A high-resolution atlas of nucleosome occupancy in yeast," Nature Genetics, vol. 39, no. 10, pp. 1235–1244, 2007.
[28] B. Li,M. Carey, and J. L.Workman, "The role of chromatin during transcription," Cell, vol. 128, no. 4, pp. 707–719, 2007.
[29] C. L. Liu, T. Kaplan, M. Kim, S. Buratowski, S. L. Schreiber, N. Friedman, and O. J. Rando, "Single-nucleosome mapping of histone modifications in S. cerevisiae," PLoS Biology, vol. 3, no. 10, p. e328, 2005.
[30] M. Marques, L. Laflamme, A. L. Gervais, and L. Gaudreau, "Reconciling the positive and negative roles of histone H2A. Z in gene transcription," Epigenetics, vol. 5, no. 4, pp. 267–272, 2010.
[31] C. Martin and Y. Zhang, "The diverse functions of histone lysine methylation," Nature Reviews Molecular Cell Biology, vol. 6, no. 11, pp. 838–849, 2005.
[32] H.-W. Mewes, D. Frishman, U. G¨uldener, G. Mannhaupt, K. Mayer, M. Mokrejs, B. Morgenstern, M. M¨unsterk¨otter, S. Rudd, and B. Weil, "MIPS: a database for genomes and protein sequences," Nucleic Acids Research, vol. 30, no. 1, pp. 31–34, 2002.
[33] C. B. Millar and M. Grunstein, "Genome-wide patterns of histone modifications in yeast," Nature Reviews Molecular Cell Biology, vol. 7, no. 9, pp. 657–666, 2006.
[34] T. Miller, N. J. Krogan, J. Dover, H. Erdjument-Bromage, P. Tempst, M. Johnston, J. F. Greenblatt, and A. Shilatifard, "COMPASS: a complex of proteins associated with a trithorax-related SET domain protein," Proceedings of the National Academy of Sciences, vol. 98, no. 23, pp. 12902–12907, 2001.
[35] M. Noll and R. D. Kornberg, "Action of micrococcal nuclease on chromatin and the location of histone H1," Journal of Molecular Biology, vol. 109, no. 3, pp. 393–404, 1977.
[36] T. R. O’Connor and J. J. Wyrick, "ChromatinDB: a database of genome-wide histone modification patterns for Saccharomyces cerevisiae," Bioinformatics, vol. 23, no. 14, pp. 1828–1830, 2007.
[37] D. K. Pokholok, C. T. Harbison, S. Levine, M. Cole, N. M. Hannett, T. I. Lee, G. W. Bell, K.Walker, P. A. Rolfe, E. Herbolsheimer, et al., "Genome-widemap of nucleosome acetylation and methylation in yeast," Cell, vol. 122, no. 4, pp. 517–527, 2005.
[38] O. J. Rando, "Combinatorial complexity in chromatin structure and function: revisiting the histone code," Current Opinion in Genetics and Development, vol. 22, no. 2, pp. 148– 155, 2012.
[39] O. J. Rando and F.Winston, "Chromatin and transcription in yeast," Genetics, vol. 190, no. 2, pp. 351–387, 2012.
[40] T. J. Richmond and C. A. Davey, "The structure of DNA in the nucleosome core," Nature, vol. 423, no. 6936, pp. 145–150, 2003.
[41] A. Ruepp, A. Zollner, D. Maier, K. Albermann, J. Hani, M. Mokrejs, I. Tetko, U. G'uldener, G. Mannhaupt, M. M¨unsterk¨otter, et al., "The FunCat, a functional annotation scheme for systematic classification of proteins from whole genomes," Nucleic Acids Research, vol. 32, no. 18, pp. 5539–5545, 2004.
[42] J. M. Schulze, T. Hentrich, S. Nakanishi, A. Gupta, E. Emberly, A. Shilatifard, and M. S. Kobor, "Splitting the task: Ubp8 and Ubp10 deubiquitinate different cellular pools of H2BK123," Genes and Development, vol. 25, no. 21, pp. 2242–2247, 2011.
[43] M. Shogren-Knaak, H. Ishii, J.-M. Sun, M. J. Pazin, J. R. Davie, and C. L. Peterson, "Histone H4-K16 acetylation controls chromatin structure and protein interactions," Science, vol. 311, no. 5762, pp. 844–847, 2006.
[44] B. D. Strahl, P. A. Grant, S. D. Briggs, Z.-W. Sun, J. R. Bone, J. A. Caldwell, S. Mollah, R. G. Cook, J. Shabanowitz, D. F. Hunt, et al., "Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression," Molecular and Cellular Biology, vol. 22, no. 5, pp. 1298–1306, 2002.
[45] G. J. Upton, "Fisher’s exact test," Journal of the Royal Statistical Society. Series A. Statistics in Society, vol. 155, no. 3, pp. 395–402, 1992.
[46] H. van Attikum, O. Fritsch, B. Hohn, and S. M. Gasser, "Recruitment of the INO80 complex by H2A phosphorylation links ATP-dependent chromatin remodeling with DNA double-strand break repair," Cell, vol. 119, no. 6, pp. 777–788, 2004.
[47] B. J. Venters and B. F. Pugh, "How eukaryotic genes are transcribed," Critical Reviews in Biochemistry and Molecular Biology, vol. 44, no. 2-3, pp. 117–141, 2009.
[48] M. T. A. B. J. P. S. A. J. P. R. N. J. C. H.-W. C. P. B. Venters BJ,Wachi S, "A comprehensive genomic bindingmap of gene and chromatin regulatory proteins in Saccharomyces," Molecular Cell, vol. 41, no. 4, pp. 480–492, 2011.
[49] X. Zhang, Y. V. Bernatavichute, S. Cokus, M. Pellegrini, S. E. Jacobsen, et al., "Genome-wide analysis of mono-, di-and trimethylation of histone H3 lysine 4 in Arabidopsis thaliana," Genome Biol, vol. 10, no. 6, p. R62, 2009.
[50] J. Zlatanova and A. Thakar, "H2A. Z: view from the top," Structure, vol. 16, no. 2, pp. 166–179, 2008.