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Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers

Abstract

Despite the conventional distinction between them, promoters and enhancers share many features in mammals, including divergent transcription and similar modes of transcription factor binding. Here we examine the architecture of transcription initiation through comprehensive mapping of transcription start sites (TSSs) in human lymphoblastoid B cell (GM12878) and chronic myelogenous leukemic (K562) ENCODE Tier 1 cell lines. Using a nuclear run-on protocol called GRO-cap, which captures TSSs for both stable and unstable transcripts, we conduct detailed comparisons of thousands of promoters and enhancers in human cells. These analyses identify a common architecture of initiation, including tightly spaced (110 bp apart) divergent initiation, similar frequencies of core promoter sequence elements, highly positioned flanking nucleosomes and two modes of transcription factor binding. Post-initiation transcript stability provides a more fundamental distinction between promoters and enhancers than patterns of histone modification and association of transcription factors or co-activators. These results support a unified model of transcription initiation at promoters and enhancers.

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Figure 1: GRO-cap identifies TSSs in promoters and enhancers.
Figure 2: Comparison of GRO-cap with CAGE.
Figure 3: TSS identification and classification.
Figure 4: Histone marks at enhancers and promoters scale with Pol II intensity.
Figure 5: Architecture of TSS pairs.
Figure 6: Modes of transcription factor binding at TSS pairs.
Figure 7: Determinants of RNA stability for both promoters and enhancers.
Figure 8: Summary of transcription initiation at regulatory regions.

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Acknowledgements

Research reported in this publication was supported by NIGMS (National Institute of General Medical Sciences) and NHGRI (National Human Genome Research Institute) grants from the US National Institutes of Health under award numbers GM25232 to J.T.L. and HG0070707 to A.S. and J.T.L., respectively. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.

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L.J.C. and J.T.L. designed the experiments. L.J.C. and C.T.W. produced the data sets. A.L.M. designed and implemented software for data analysis. A.L.M., L.J.C., A.S., J.T.L. and C.G.D. analyzed the data and interpreted the results. L.J.C., A.L.M., A.S., J.T.L. and C.G.D. wrote the manuscript.

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Correspondence to Adam Siepel or John T Lis.

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A unified architecture of initiation regions at mammalian promoters and enhancers. (ZIP 2685 kb)

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Core, L., Martins, A., Danko, C. et al. Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nat Genet 46, 1311–1320 (2014). https://doi.org/10.1038/ng.3142

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