Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome

Abstract

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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Figure 1: Features of human transcriptional promoters and enhancers.
Figure 2: Prediction of promoters based on chromatin signatures.
Figure 3: Prediction of enhancers based on chromatin signatures.
Figure 4: Identification of a putative novel enhancer for SLC22A5.
Figure 5: Validation of the prediction model by STAT1 binding and reporter assays.

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Acknowledgements

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.

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Authors

Contributions

N.D.H., B.R. and R.D.G. designed the transcription factor and histone ChIP-chip experiments; G.E.C. designed and performed the DNase-chip experiments; N.D.H., R.K.S., C.W.C., R.D.H. and S.V.C. conducted the ChIP-chip experiments; N.D.H., G.H., L.O.B., K.A.C. and C.Q. analyzed the microarray data; G.H., N.D.H., B.R. and W.W. conceived and developed the promoter and enhancer prediction method. Independently, Y.F. and Z.W. discovered the promoter-associated chromatin signatures. N.D.H. and B.R. wrote the manuscript.

Corresponding author

Correspondence to Bing Ren.

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R.D.G. is an employee of NimbleGen Systems, Inc.

Supplementary information

Supplementary Fig. 1

ChIP-chip profiles at a representative promoter. (PDF 336 kb)

Supplementary Fig. 2

Cluster analysis in IFNγ-treated HeLa cells. (PDF 600 kb)

Supplementary Fig. 3

p300 binding distribution and DNaseI hypersensitivity. (PDF 330 kb)

Supplementary Fig. 4

Distribution of predicted enhancers in IFNγ-treated HeLa cells. (PDF 293 kb)

Supplementary Fig. 5

Prediction of a known enhancer, HS2, in the human β-globin locus. (PDF 371 kb)

Supplementary Fig. 6

Cross-validation of optimal histone modifications for prediction model. (PDF 362 kb)

Supplementary Table 1

Summary of RNAP ChIP-chip validation. (XLS 32 kb)

Supplementary Table 2

TSS classes from promoter clustering. (XLS 101 kb)

Supplementary Table 3

p300 binding sites. (XLS 69 kb)

Supplementary Table 4

DNaseI hypersensitive sites. (XLS 109 kb)

Supplementary Table 5

High-confidence prediction sets. (XLS 388 kb)

Supplementary Table 6

TRAP220 binding sites. (XLS 36 kb)

Supplementary Table 7

STAT1 binding sites. (XLS 24 kb)

Supplementary Methods (PDF 135 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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