Genome-wide mapping of histone modifications

National Heart, Lung, And Blood Institute

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Abstract

Histone modifications are implicated in influencing gene expression. To map the human epigenomes at high resolution, we have developed a technique termed ChIP-Seq by combining the chromatin immunoprecipitation assays (ChIP) with the Solexa high throughput sequencing technology. We have generated high-resolution maps for the genome-wide distribution of 40 histone lysine and arginine methylations as well as histone variant H2A.Z, RNA polymerase II and the insulator binding protein CTCF across the human genome using ChIP-Seq. We have also mapped genome-wide nucleosome positions in resting and activated human T cells. Using these, we have analyzed the patterns of histone modifications in regulatory regions including promtoers and enhancers. Our data indicate that multiple modifications function together to define chromatin structure required for gene regulation. Our data provide new insights into the function of histone modifications and chromatin organization in genome function. To understand how the histone modification patterns are established and regulated, we determined the genome-wide profiles of 5 HATs and 4 HDACs in human CD4+ T cells. The acetylation of histones is associated with active transcription and in general HAT binding has been associated with active genes while HDAC binding has been associated with inactive genes. Our results reveal that both HATs and HDACs are found at active genes with acetylated histones. Our data provide evidence that HATs and HDACs are both targeted to transcribed regions of active genes by phosphorylated RNA Pol II. Furthermore, the majority of HDACs in the human genome function to reset chromatin by removing acetylation at active genes. Inactive genes that are primed by MLL-mediated histone H3K4 methylation are subject to a dynamic cycle of acetylation and deacetylation by transient HAT/HDAC binding, preventing Pol II from binding to these genes but poising them for future activation.