Single-cell and single-molecule epigenomics to uncover genome regulation at unprecedented resolution

Abstract

Recent advances in single-cell and single-molecule epigenomic technologies now enable the study of genome regulation and dynamics at unprecedented resolution. In this Perspective, we highlight some of these transformative technologies and discuss how they have been used to identify new modes of gene regulation. We also contrast these assays with recent advances in single-cell transcriptomics and argue for the essential role of epigenomic technologies in both understanding cellular diversity and discovering gene regulatory mechanisms. In addition, we provide our view on the next generation of biological tools that we expect will open new avenues for elucidating the fundamental principles of gene regulation. Overall, this Perspective motivates the use of these high-resolution epigenomic technologies for mapping cell states and understanding regulatory diversity at single-molecule resolution within single cells.

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Fig. 1: Dynamic regulatory changes in development.
Fig. 2: Cis and trans modes of regulatory heterogeneity.
Fig. 3: Future approaches for uncovering single-cell regulatory principles.

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Acknowledgements

We thank L. Gaskell for insightful comments throughout the composition of this manuscript. E.S. is supported by the Jane Coffin Childs Memorial Fund for Medical Research. B.E.B. is an American Cancer Society Research Professor and is supported by funds from the National Human Genome Research Institute, the National Cancer Institute and the NIH Common Fund. J.D.B. acknowledges support from the Harvard Society of Fellows and Broad Institute Fellowship. J.D.B also acknowledges the Allen Institute and the NIH R21HG009749 for funding.

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E.S., B.E.B. and J.D.B conceived and wrote the manuscript.

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Correspondence to Jason D. Buenrostro.

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E.S., B.E.B. and J.D.B have filed patents covering single-cell or single-molecule technologies. B.E.B. owns equity in Fulcrum Therapeutics, 1CellBio Inc, Nohla Therapeutics and HiFiBio Inc., and is an advisor for Fulcrum Therapeutics, HiFiBio Inc and Cell Signaling Technologies.

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Shema, E., Bernstein, B.E. & Buenrostro, J.D. Single-cell and single-molecule epigenomics to uncover genome regulation at unprecedented resolution. Nat Genet 51, 19–25 (2019). https://doi.org/10.1038/s41588-018-0290-x

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