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Combinatorial Patterns of Histone Acetylations and Methylations in the Human Genome

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Combinatorial Patterns of Histone Acetylations and Methylations in the Human Genome LETTERS Combinatorial patterns of histone acetylations and methylations in the human genome Zhibin Wang1,5, Chongzhi Zang2,5, Jeffrey A Rosenfeld3–5, Dustin E Schones1, Artem Barski1, Suresh Cuddapah1, Kairong Cui1, Tae-Young Roh1, Weiqun Peng2, Michael Q Zhang3 & Keji Zhao1 Histones are characterized by numerous posttranslational level (see Methods section for data deposition), and analyzed these modifications that influence gene transcription1,2. However, together with the H2A.Z and 19 histone methylation maps we because of the lack of global distribution data in higher generated previously15. eukaryotic systems3, the extent to which gene-specific We first systematically evaluated the specificities of the acetylation combinatorial patterns of histone modifications exist remains antibodies used in this study (Supplementary Methods, Supplemen- to be determined. Here, we report the patterns derived from tary Table 1 and Supplementary Fig. 1 online). Competition assays the analysis of 39 histone modifications in human CD4+ using modified and unmodified peptides indicated that most anti- http://www.nature.com/naturegenetics T cells. Our data indicate that a large number of patterns bodies showed specificity for the desired acetylation (Supplementary are associated with promoters and enhancers. In particular, Fig. 1). The H4K5ac and H3K4ac antibodies demonstrated some we identify a common modification module consisting of 17 crossreactivity toward H4K12ac and H3K9ac, respectively, in a con- modifications detected at 3,286 promoters. These modifications dition with excess competitor peptides (Supplementary Fig. 1d,j), tend to colocalize in the genome and correlate with each other and the H4K91ac antibody did not work in protein blotting. Thus, the at an individual nucleosome level. Genes associated with this results for these modifications should be interpreted with caution. Of module tend to have higher expression, and addition of more note, H2AK9ac has not been reported previously, and H3K4ac has modifications to this module is associated with further only been identified by mass-spectrometry analysis and has not been increased expression. Our data suggest that these histone previously characterized functionally16. Protein blotting indicated that modifications may act cooperatively to prepare chromatin these acetylations indeed exist in human CD4+ T cells (Supplemen- for transcriptional activation. tary Fig. 1j,o). We previously analyzed the genome-wide distribution of H2BK5me1 (ref. 15), and protein blotting data in this study Histones are subject to numerous covalent modifications, including indicated that this methylation exists in human cells and that the © Group 2008 Nature Publishing methylation and acetylation, that occur mainly at their N-terminal H2BK5me1 antibody is specific (Supplementary Fig. 1p). tails and that can affect transcription of genes1,2,4,5. Extensive studies Next, we determined the genomic distribution patterns of these have established that histone acetylation is primarily associated with histone acetylations using the ChIP-Seq technique15, which we pre- gene activation, whereas methylation, depending on its position and viously confirmed yields H3K4me3 distribution patterns similar to state, is associated with either repression or activation5–10. Various those generated by the ChIP-SAGE (GMAT) strategy15,17. To validate models, including the histone code, the signaling network and the the histone acetylation data, we compared the genomic distribution charge neutralization model, have been proposed to account for the patterns of the K9/K14-diacetylated histone H3 from ChIP-SAGE18 function of histone modifications11–14. The histone code hypothesis with the separately examined patterns of H3K9ac and H3K14ac in suggests that multiple histone modifications act in a combinatorial this study (Supplementary Fig. 2 online). We found that the ChIP- fashion to specify distinct chromatin states. However, the extent to Seq acetylation data are reliable and that the previously observed which combinatorial patterns of histone modifications exist in H3K9/K14 diacetylation patterns could be primarily attributed to the genome is unknown. We have now produced genome-wide H3K9 acetylation. maps of 18 histone acetylations (H2AK5ac, H2AK9ac, H2BK5ac, To examine the distribution of the histone acetylations at different H2BK12ac, H2BK20ac, H2BK120ac, H3K4ac, H3K9ac, H3K14ac, functional regions, we generated composite profiles for the region H3K18ac, H3K23ac, H3K27ac, H3K36ac, H4K5ac, H4K8ac, spanning the transcription start sites (TSSs; Fig. 1a–c and Supple- H4K12ac, H4K16ac and H4K91ac) at an individual nucleosome mentary Fig. 3 online) or the entire gene bodies and extending 5 kb 1Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, Maryland 20892, USA. 2Department of Physics, The George Washington University, Washington, D.C. 20052, USA. 3Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. 4Department of Biology, New York University, New York, New York 10003, USA. 5These authors contributed equally to this work. Correspondence should be addressed to K.Z. ([email protected]). Received 19 December 2007; accepted 1 April 2008; published online 15 June 2008; doi:10.1038/ng.154 NATURE GENETICS ADVANCE ONLINE PUBLICATION 1 LETTERS a d g H3K9ac H3K9ac ZMYND8 1.2E–07 High Chr20: Medium 8E–09 45250000 45300000 45350000 45400000 45450000 1E–07 High H3K4me3 96 Low 7E–09 Silent * H3K4me2 34 8E–08 Silent 6E–09 * H3K4me1 61 5E–09 * 6E–08 H3K4ac 18 4E–09 * H3K27me3 6 3E–09 4E–08 H3K27me2 5 2E–09 H3K27me1 15 Normalized counts 2E–08 Normalized counts 1E–09 * H3K27ac 54 * 0 0 H3K9me3 3 –2,000 –1,0000 1,000 2,000 0.1 0.2 0.3 0.4 0.500.600.700.800.90 H3K9me2 5 5 kb up txStart txEnd Position relative to TSS 2.5 kb up H3K9me1 32 5 kb down * 2.5 kb down H3K9ac 21 b e * H3K79me3 31 H3K23ac H3K23ac * 1.4E–08 High 2E–09 H3K79me2 25 High * 1.2E–08 Medium H3K79me1 13 Silent * Low H3R2me2 6 1E–08 1.5E–09 Silent H3R2me1 6 8E–09 1E–09 H3K36me3 25 6E–09 H3K36me1 6 H3K36ac 16 4E–09 5E–10 * H4K20me3 4 Normalized counts 2E–09 H4K20me1 29 0 0 H2BK5me1 35 0.1 0.2 0.3 0.4 –10,000 –5,0000 5,000 10,000 0.500.600.700.800.90 H2BK5ac 41 5 kb up txStart txEnd * 2.5 kb up H4R3me2 5 Position relative to TSS 5 kb down 2.5 kb down H3K14ac 5 * cf H3K18ac 47 H4K12ac H4K12ac * 2E–09 H3K23ac 10 1.6E–08 High High * H4K5ac 46 1.4E–08 Medium Silent * 1.5E–09 H4K8ac 47 * 1.2E–08 Low H4K12ac 8 1E–08 Silent * H4K16ac 12 1E–09 * 8E–09 H4K91ac 35 * 6E–09 H2BK12ac 9 5E–10 * H2BK20ac 22 4E–09 Normalized counts Normalized counts * H2BK120ac 24 Normalized counts 2E–09 0 * H2AK5ac 10 0.1 0.2 0.3 0.4 0 0.500.600.700.800.90 H2AK9ac 4 –10,000 –5,0000 5,000 10,000 5 kb up txStart txEnd 2.5 kb up H2A.Z 39 5 kb down * Position relative to TSS 2.5 kb down Figure 1 Three distribution patterns of histone acetylations. (a–c) Normalized tag counts of histone acetylation signals surrounding the TSS were indicated http://www.nature.com/naturegenetics for highly active, intermediately active (two levels) and silent genes. Each group represents 1,000 genes with similar expression, as described in Methods. (d–f) Normalized tag counts of histone acetylation signals of 1,000 highly active or silent genes across the gene bodies. The plots extend 5 kb 5¢ and 3¢ of the genic regions (see Methods). txStart, transcription start site; txEnd, transcription end. (g) Chromatin modification patterns at the ZMYND8 (PRKCBP1) gene locus. Significant modifications in the –1 kb to +1 kb region surrounding the TSS (P o 10À7; highlighted in red) are indicated by asterisks on the left. upstream and 5 kb downstream for groups of 1,000 genes according to H4K5ac, H4K8ac, H4K12ac and H4K16ac are elevated in the promoter their expression (Fig. 1d–f and Supplementary Fig. 4 online). We and transcribed regions of active genes (Fig. 1f and Supplementary found that all acetylations positively correlated with gene expression, Fig. 4). These results are consistent with previous reports that specific consistent with their involvement in tran- scriptional activation. However, our data indicate that different acetylations may target a c 2 10,000 different regions of genes. For example, 1.5 H2AK9ac, H2BK5ac, H3K9ac, H3K18ac, 1,000 1 © Group 2008 Nature Publishing H3K27ac, H3K36ac and H4K91ac are mainly 0.5 ) located in the region surrounding the TSS 100 2 0 (log (Fig. 1d and Supplementary Fig. 4), whereas patterns –0.5 10 H2BK12ac, H2BK20ac, H2BK120ac, H3K4ac, –1 Number of combinatorial –1.5 1 Fold change in expression 1 10 100 1,000 10,000 Number of genes associated H2A.Z H4K5ac H4K8ac with the same pattern H3K4ac H3K9ac H4K12ac H4K16ac H4K91ac H3K14ac H3K18ac H3K23ac H3K27ac H3K36ac H2AK9ac H2AK5ac H2BK5ac H3K4me1 H3K4me2 H3K4me3 H3K9me1 H3K9me2 H3K9me3 Figure 2 Patterns of histone modifications H3R2me1 H3R2me2 H2BK12ac H2BK20ac H4K20me1 H4K20me3 H3K27me1 H3K27me2 H3K27me3 H3K36me1 H3K36me3 H3K79me1 H3K79me2 H3K79me3 H2BK5me1 associated with promoters. (a) Patterns of histone b 100 H2BK120ac modifications at promoters. The y axis indicates B,H2AK9ac,H2BK5me1,H3K79me1,me2,me3,H4K12ac,H4K16ac,H4K20me1:62 90 B,H2AK9ac,H2BK5me1,H3K79me1,me2,me3,H4K16ac,H4K20me1:68 III the number of patterns of 39 histone B,H2BK5me1,H3K79me1,me2,me3,H4K16ac,H4K20me1:74 modifications (see Methods), and the x axis 80 B,H4K16ac:67 B:64 II indicates the number of promoters associated 70 H3K36me3:135 with each pattern. (b) Correlation of gene H2AZ,H3K4me1,me2,me3,H3K9me1,H3K27me3:77 H2AZ,H3K4me2,me3,H3K9me1,H3K27me3:70 expression with the thirteen most prevalent 60 H2AZ,H3K4me3,H3K27me3:74 I modification patterns. B, the 17-modification H3K4me3,H3K27me3:167 50 H3K4me3:85 backbone; All, all genes. The number of H3K27me3:630 promoters within each pattern is also indicated.
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