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. Chromatin modifications have been implicated in regulation of gene expression. While association of certain modifications with expressed or silent genes has been established, it remains unclear how changes in chromatin environment relate to changes in gene expression. We used ChIP-Seq to analyze the genome-wide changes in chromatin modifications during activation of total CD4+ T cells by T cell receptor (TCR) signaling. We found that the chromatin modification patterns at many induced and silenced genes are relatively stable during the short-term activation of resting T cells. Active chromatin modifications were already in place for a majority of inducible protein-coding genes even while the genes were silent in resting cells. Similarly, genes that were silenced upon T cell activation retained positive chromatin modifications even after being silenced. To investigate if these observations are also valid for miRNA-coding genes, we systematically identified promoters for known miRNA genes using epigenetic marks and profiled their expression patterns using deep sequencing. We found that chromatin modifications can poise miRNA-coding genes as well. Our data suggest that miRNA and protein-coding genes share similar mechanisms of regulation by chromatin modifications, which poise inducible genes for activation in response to environmental stimuli.