Eukaryotic gene transcription is accompanied by acetylation and methylation of nucleosomes near promoters, but the locations and roles of histone modifications elsewhere in the genome remain unclear. We determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of Lys4 of histone H3 (H3K4), whereas enhancers are marked by monomethylation, but not trimethylation, of H3K4. We developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). Our results give insight into the connections between chromatin modifications and transcriptional regulatory activity and provide a new tool for the functional annotation of the human genome.
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We thank J. Kadonaga, X. Fu and members of the Ren lab for comments. This work was supported by funding from the Ludwig Institute for Cancer Research (B.R.), the National Human Genome Research Institute (B.R., Z.W. and R.D.G.) and the National Cancer Institute (B.R.). Requests for materials should be addressed to B.R.
R.D.G. is an employee of NimbleGen Systems, Inc.
ChIP-chip profiles at a representative promoter. (PDF 336 kb)
Cluster analysis in IFNγ-treated HeLa cells. (PDF 600 kb)
p300 binding distribution and DNaseI hypersensitivity. (PDF 330 kb)
Distribution of predicted enhancers in IFNγ-treated HeLa cells. (PDF 293 kb)
Prediction of a known enhancer, HS2, in the human β-globin locus. (PDF 371 kb)
Cross-validation of optimal histone modifications for prediction model. (PDF 362 kb)
Summary of RNAP ChIP-chip validation. (XLS 32 kb)
TSS classes from promoter clustering. (XLS 101 kb)
p300 binding sites. (XLS 69 kb)
DNaseI hypersensitive sites. (XLS 109 kb)
High-confidence prediction sets. (XLS 388 kb)
TRAP220 binding sites. (XLS 36 kb)
STAT1 binding sites. (XLS 24 kb)
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Heintzman, N., Stuart, R., Hon, G. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39, 311–318 (2007). https://doi.org/10.1038/ng1966
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