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Landscape of monoallelic DNA accessibility in mouse embryonic stem cells and neural progenitor cells

Nature Genetics volume 49, pages 377386 (2017) | Download Citation

  • A Corrigendum to this article was published on 26 May 2017

This article has been updated

Abstract

We developed an allele-specific assay for transposase-accessible chromatin with high-throughput sequencing (ATAC–seq) to genotype and profile active regulatory DNA across the genome. Using a mouse hybrid F1 system, we found that monoallelic DNA accessibility across autosomes was pervasive, developmentally programmed and composed of several patterns. Genetically determined accessibility was enriched at distal enhancers, but random monoallelically accessible (RAMA) elements were enriched at promoters and may act as gatekeepers of monoallelic mRNA expression. Allelic choice at RAMA elements was stable across cell generations and bookmarked through mitosis. RAMA elements in neural progenitor cells were biallelically accessible in embryonic stem cells but premarked with bivalent histone modifications; one allele was silenced during differentiation. Quantitative analysis indicated that allelic choice at the majority of RAMA elements is consistent with a stochastic process; however, up to 30% of RAMA elements may deviate from the expected pattern, suggesting a regulated or counting mechanism.

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Change history

  • 13 February 2017

    In the version of this article initially published online, there were two errors. In the section “Three classes of monoallelic elements” in the main text, "We classified all monoallelically accessible elements (1,966 elements)" should have read "1,964 elements." In the legend for Figure 5c, the number of elements open in ESCs should have been given as 234 instead of 35. The errors have been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

We thank J. Dekker for sharing Hi-C data before publication and for feedback, and J. Pritchard, A. Urban and members of our laboratories for advice. This work was supported by the US National Institutes of Health (NIH; P50-HG007735 to H.Y.C. and W.J.G.). The Heard labratory is “Equipe labellisée par la Ligue Nationale Contre le Cancer” and is supported by a European Research Council (ERC) Advanced Investigator Award; Labex DEEP (ANR-11-LBX-0044) part of the IDEX Idex PSL (ANR-10-IDEX-0001-02 PSL).

Author information

Author notes

    • Jin Xu
    •  & Ava C Carter

    These authors contributed qually to this work.

Affiliations

  1. Center for Personal Dynamic Regulomes, Stanford University, Stanford, California, USA.

    • Jin Xu
    • , Ava C Carter
    • , William J Greenleaf
    •  & Howard Y Chang
  2. Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, Paris, France.

    • Anne-Valerie Gendrel
    • , Mikael Attia
    •  & Edith Heard
  3. Data Sciences and Statistics, Stanford University School of Medicine, Stanford, California, USA.

    • Joshua Loftus
    •  & Robert Tibshirani
  4. Departement of Genetics, Stanford University School of Medicine, Stanford, California, USA.

    • William J Greenleaf

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Contributions

J.X., A.C.C., E.H. and H.Y.C. conceived the project. J.X. wrote the allele-specific ATAC–seq analysis pipeline and did most of the data analysis, and A.C.C. performed all experiments, generated ATAC–seq libraries and did some data analysis. A.-V.G., M.A. and E.H. provided cell lines and conceptual input. J.L. and R.T. helped design statistical analysis and permutations for the allele-specific ATAC–seq pipeline. W.J.G. provided insight and helped design experiments. H.Y.C. supervised the project and wrote the paper with J.X. and A.C.C.

Competing interests

H.Y.C. and W.J.G. are co-founders of Epinomics. Stanford University has filed a patent on ATAC–seq, on which H.Y.C. and W.J.G. are inventors.

Corresponding author

Correspondence to Howard Y Chang.

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DOI

https://doi.org/10.1038/ng.3769

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