組蛋白的後轉譯修飾（Post-translational modification）在調控基因轉錄（Transcription）上扮演極為重要的角色，這些修飾包含乙醯化（Acetylation）、甲基化（Methylation）及泛素化（Ubiquitination）等……，它們改變染色質（Chromatin）結構並產生染色質調節因子的結合位點。在表徵遺傳學的研究中，我們需要一個可以對基因列表進行生物顯著性分析（Biological significance analysis）的工具，在許多文獻當中有著許多的組蛋白修飾及染色質調節因子研究的ChIP-chip實驗數據，然而並沒有一個工具將這些資料進行統整，並且進行上述的分析，因此，我們開發了YHMI（Yeast Histone Modification Identifier）網頁工具，整合了15種酵母中的組蛋白修飾，以及83個染色質重塑因子所調控（Chromatin remodeling factor）的蛋白，YHMI可以針對這15個組蛋白修飾、83個蛋白，對一份基因列表進行顯著性分析，分析出啟動子（Promoter）及編碼區（Coding Region）是否顯著富集或是顯著缺乏特定的組蛋白修飾，而83個蛋白則是只對啟動子進行分析，最後以圖形及表格分別呈現。
為了驗證YHMI的分析結果有其參考價值，在最後分別以「分析高轉錄基因中的組蛋白修飾特徵」及「分析Esa1結合基因中的組蛋白修飾特徵」兩個實例進行討論，說明了YHMI分析的準確性及其分析結果提供許多可測試的假設作為研究的使用。我們相信YHMI會是個有利於生物學家進行表徵遺傳學研究的工具。YHMI網址：http://cosbi4.ee.ncku.edu.tw/YHMI/home/。

Post-translation modifications of histones, which including acetylation, methylation, ubiquitination and the others, play an important role in regulating gene expression. These post-translation modifications alter chromatin structure and create binding sites of chromatin regulators.
In the research of epigenetics, to analyze (1) which histone modifications exist in a gene list, and (2) how these histone modifications are enriched or depleted, a tool must be needed. There are a lot of ChIP-chip datasets of histone modifications and chromatin regulators in yeast, which are scattered in some literatures, but there is not a tool investigating these data and conducting an analysis. Thus, we developed the YHMI (Yeast Histone Modifications Identifier) web tool, which collected 15 histone modifications and 83 protein regulated by chromatin remodeling factors, and is able to identify enriched or depleted histone modifications and chromatin regulators for a list of yeast genes. Results of YHMI are showed in figures and tables.
Finally, we used two case studies which are “analysis of highly transcribed genes” and “analysis of genes bound by Esa1” to demonstrate high quality and biological insight of YHMI. Therefore, we believe that YHMI will help biologists to do epigenetics research.
Now, YHMI is available online at: http://cosbi4.ee.ncku.edu.tw/YHMI/home/

W. CH, "The epigenotype," Endeavour, vol. 1, pp. 18-20, 1942.
H. R, “Mechanisms for the control of gene activity during development,” Biol Rev Camb Philos Soc, 第 冊65, 編號 4, pp. 431-471, 1990.
Cox M, Nelson DR, and Lehninger AL, Lehninger Principles of Biochemistry, San Francisco: W.H. Freeman, 2005.
Redon C, Pilch D, Rogakou E, Sedelnikova O, Newrock K, and Bonner W, "Histone H2A variants H2AX and H2AZ.," Current Opinion in Genetics & Development, vol. 12, no. 2, p. 162–169, 4 2002.
Bhasin M, Reinherz EL, and Reche PA, "Recognition and classification of histones using support vector machine," Journal of Computational Biology., vol. 13, no. 1, pp. 102-112, 2006.
Grunstein, M., "Histone function in transcription," Annu. Rev. Cell Biol., vol. 6, pp. 643-678, 1990.
Jenuwein T, Allis CD, "Translating the histone code," Science, vol. 293 , no. 5532, pp. 1074-1080, 8 2001.
Smith, C. M. et al., "Mass spectrometric quantification of acetylation at specific lysines within the amino-aminoterminal," Anal. Biochem, pp. 23-33, 2003.
Boyne, M. T. 2nd, Pesavento, J. J., Mizzen, C. A. and Kelleher, N. L., "Precise characterization of human histones in the H2A gene family by top down mass.," J. Proteome Res., vol. 5, pp. 248-253, 2006.
Clarke, D. J., O’Neill, L. P. and Turner, B. M., "Selective use of H4 acetylation sites in the yeast Saccharomyces," cerevisiae. Biochem. J., vol. 294, pp. 557-561, 1993.
Rayasam, G. V. et al., "NSD1 is essential for early post-implantation development and has a catalytically active SET domain.," EMBO J., vol. 22, pp. 3153-3163, 2003.
Wang, A., Kurdistani, S. K. & Grunstein, M., "Requirement of Hos2 histone deacetylase for gene activity in yeast.," Science, vol. 298, pp. 1412-1414, 2002.
J. E. Krebs, "Moving marks: dynamic histone modifications in yeast," Mol. Biosyst., vol. 3, pp. 590-597, 2007.
Babiarz, J. E., J. E. Halley, and J. Rine, "Telomeric heterochromatin boundaries require NuA4-dependent acetylation of histone variant H2A.Z in Saccharomyces cerevisiae.," Genes Dev., vol. 20, pp. 700-710, 2006.
Keogh, M. C., T. A. Mennella, C. Sawa, S. Berthelet, N. J. Krogan et al., "The Saccharomyces cerevisiae histone H2A variant Htz1 is acetylated by NuA4.," Genes Dev, vol. 20, pp. 660-665, 2006.
Millar, C. B., and M. Grunstein, "Genome-wide patterns of histone modifications in yeast.," Nat. Rev. Mol. Cell Biol., vol. 7, pp. 657-666, 2006.
Nathan, D., K. Ingvarsdottir, D. E. Sterner, G. R. Bylebyl, M. Dokmanovic et al., "Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications.," Genes Dev., vol. 20, pp. 996-976, 2006.
Hyland, E. M., H. Molina, K. Poorey, C. Jie, Z. Xie et al., "An evolutionarily ‘young’ lysine residue in histone H3 attenuates transcriptional output in Saccharomyces cerevisiae.," Genes Dev., vol. 25, pp. 1306-1319, 2011.
Grant, P. A., L. Duggan, J. Cote, S. M. Roberts, J. E. Brownell et al., "Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex.," Genes Dev., vol. 11, pp. 1640-1650, 1997.
Rando, O.J., Winston, F., "Chromatin and transcription in yeast.," Genetics, vol. 190, pp. 351-387, 2012.
Koutelou, E., C. L. Hirsch, and S. Y. Dent, "Multiple faces of the SAGA complex," Curr. Opin. Cell Biol, vol. 22, pp. 374-382, 2010.
David E. Sterner, Xun Wang, Melissa H. Bloom, Gabriel M. Simon and Shelley L. Berger, "The SANT Domain of Ada2 Is Required for Normal Acetylation of Histones by the Yeast SAGA Complex," Journal of Biological Chemestry, pp. 8178-8186, 2002.
Allard, S., R. T. Utley, J. Savard, A. Clarke, and P. Grant et al., "NuA4, an essential transcription adaptor/histone H4 acetyltransferase complex containing Esa1p and the ATM-related cofactor Tra1p.," EMBO J., vol. 18, pp. 5108-5119, 1999.
Bird A W, Yu D Y, Pray-Grant M G, et al., "Acetylation of histone H4 by Esal is required for DNA double-strand break repair[J].," Nature, vol. 419, pp. 411-415, 2002.
Guillemette, B., Bataille, A.R., Gevry, N., et al., "Variant histone H2A.Z is globally localized to the promoters of inactive yeast genes and regulates nucleosome positioning.," PLoS Biol, p. e384, 2005.
Guillemette, B., 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.
Pokholok, D.K., Harbison, C.T., Levine, S., et al., "Genome-wide map of nucleosome acetylation and methylation in yeast.," Cell, vol. 122, pp. 517-527, 2005.
Kirmizis, A., Santos-Rosa, H., Penkett, C.J., et al., "Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation.," Nature, vol. 449, pp. 928-932, 2007.
Schulze, J.M., Hentrich, T., Nakanishi, S., et al., "Splitting the task: Ubp8 and Ubp10 deubiquitinate different cellular pools of H2BK123.," Genes Dev, vol. 25, pp. 2242-2247, 2011.
Venters, B.J., Wachi, S., Mavrich, T.N., et al., "A comprehensive genomic binding map of gene and chromatin regulatory proteins in Saccharomyces.," Mol Cell, vol. 41, pp. 480-492, 2011.
Cherry, J.M., Hong, E.L., Amundsen, C., et al., "Saccharomyces Genome Database: the genomics resource of budding yeast.," Nucleic Acids Res, vol. 40, pp. D700-705, 2012.
Hung, P., Yang, T., Liaw, H., et al., "The Yeast Nucleosome Atlas (YNA) database: an integrative gene mining platform for studying chromatin structure and its regulation in yeast.," BMC Genomics., vol. 15, p. S5., 2014.
O'Connor, T.R., Wyrick, J.J., "ChromatinDB: a database of genome-wide histone modification patterns for Saccharomyces cerevisiae.," Bioinformatics, vol. 23, pp. 1828-1830, 2007.
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.
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.
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.
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 Ara- bidopsis thaliana," Genome Biol, vol. 10, no. 6, p. R62, 2009.
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.
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.
B. Li, M. Carey, and J. L. Workman, "The role of chromatin during transcription," Cell, vol. 128, no. 4, pp. 707-719, 2007.
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.
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 with- out a SET domain," Current Biology, vol. 12, no. 12, pp. 1052-1058, 2002.
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 Sci- ences, vol. 98, no. 23, pp. 12902-12907, 2001.
B. D. Strahl, P. A. Grant, S. D. Briggs, Z.-W. Sun, J. R. Bone, J. A. Caldwell, S. Mol- lah, 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.
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.
J. Zlatanova and A. Thakar, "H2A. Z: view from the top," Structure, vol. 16, no. 2, pp. 166-179, 2008.
Holstege, F.C., Jennings, E.G., Wyrick, J.J., et al., "Dissecting the regulatory circuitry of a eukaryotic genome.," Cell, vol. 95, pp. 717-728, 1998.
Doyon, Y., Cote, J., "The highly conserved and multifunctional NuA4 HAT complex.," Curr Opin Genet Dev, vol. 14, pp. 147-154, 2004.
Rodriguez-Navarro, S., "Insights into SAGA function during gene expression.," EMBO Rep, vol. 10, pp. 843-850, 2009.
Ginsburg, D.S., Anlembom, T.E., Wang, J., et al., "NuA4 links methylation of histone H3 lysines 4 and 36 to acetylation of histones H4 and H3.," J Biol Chem, vol. 289, pp. 32656-32670, 2014.
Su, W.-P., Hsu, S.-H., Chia, L.-C., et al., "Combined Interactions of Plant Homeodomain and Chromodomain Regulate NuA4 Activity at DNA Double-Strand Breaks.," Geneticcs, vol. 202, pp. 77-+, 2016.
Bian, C., Xu, C., Ruan, J., et al., "Sgf29 binds histone H3K4me2/3 and is required for SAGA complex recruitment and histone H3 acetylation.," Embo j, vol. 30, pp. 2829-2842, 2011.
Wood, A., Schneider, J., Dover, J., et al., "The Bur1/Bur2 complex is required for histone H2B monoubiquitination by Rad6/Bre1 and histone methylation by COMPASS.," Mol Cell, vol. 20, pp. 589-599, 2005.
Nakanishi, S., Lee, J.S., Gardner, K.E., et al., "Histone H2BK123 monoubiquitination is the critical determinant for H3K4 and H3K79 trimethylation by COMPASS and Dot1.," J Cell Biol, vol. 186, pp. 371-377, 2009.
Gavin, A.C., Aloy, P., Grandi, P., et al., "Proteome survey reveals modularity of the yeast cell machinery.," Nature, vol. 440, pp. 631-636, 2006.
Mitchell, L., Huard, S., Cotrut, M., et al., "mChIP-KAT-MS, a method to map protein interactions and acetylation sites for lysine acetyltransferases.," Proc Natl Acad Sci U S A, vol. 110, pp. E1641-1650.
Lin, Y.Y., Lu, J.Y., Zhang, J., et al., "Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis.," Cell, vol. 136, pp. 1073-1084, 2009.
Kurat, C.F., Lambert, J.P., Petschnigg, J., et al., "Cell cycle-regulated oscillator coordinates core histone gene transcription through histone acetylation.," Proc Natl Acad Sci U S A, vol. 111, pp. 14124-14129, 2014.
Liu, Y., Xu, X., Singh-Rodriguez, S., et al., "Histone H3 Ser10 phosphorylation-independent function of Snf1 and Reg1 proteins rescues a gcn5- mutant in HIS3 expression.," Mol Cell Biol, vol. 25, pp. 10566-10579, 2005.
Lee, K.K., Sardiu, M.E., Swanson, S.K., et al., "Combinatorial depletion analysis to assemble the network architecture of the SAGA and ADA chromatin remodeling complexes.," Molecular systems biology, vol. 7, p. 503, 2011.
Li, F., Zheng, L.D., Chen, X., et al., "Gcn5-mediated Rph1 acetylation regulates its autophagic degradation under DNA damage stress.," Nucleic Acids Res, vol. 45, pp. 5183-5197, 2017.
Kim, J.H., Saraf, A., Florens, L., et al., "Gcn5 regulates the dissociation of SWI/SNF from chromatin by acetylation of Swi2/Snf2.," Genes Dev, vol. 24, pp. 2766-2771, 2010.
Papamichos-Chronakis, M., Petrakis, T., Ktistaki, E., et al., "Cti6, a PHD domain protein, bridges the Cyc8-Tup1 corepressor and the SAGA coactivator to overcome repression at GAL1.," Mol Cell, vol. 9, pp. 1297-1305, 2002.