On the existence and functionality of topologically associating domains


Genomes across a wide range of eukaryotic organisms fold into higher-order chromatin domains. Topologically associating domains (TADs) were originally discovered empirically in low-resolution Hi-C heat maps representing ensemble average interaction frequencies from millions of cells. Here, we discuss recent advances in high-resolution Hi-C, single-cell imaging experiments, and functional genetic studies, which provide an increasingly complex view of the genome’s hierarchical structure–function relationship. On the basis of these new findings, we update the definitions of distinct classes of chromatin domains according to emerging knowledge of their structural, mechanistic and functional properties.

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Fig. 1: The structural features of topologically associating domains.
Fig. 2: Chromatin domains and their boundaries are present in single cells.
Fig. 3: Evidence for and against TADs as a critical functional intermediary in the regulation of genes by developmentally active enhancers.


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We thank members of the 3D genome-folding community for helpful discussions. In particular, we gratefully acknowledge B. Ren for feedback on this work. J.E.P.-C. is supported as a New York Stem Cell Foundation—Robertson Investigator and an Alfred P. Sloan Foundation Fellow. This research was supported by The New York Stem Cell Foundation (J.E.P.-C.), the Alfred P. Sloan Foundation (J.E.P.-C.), the NIH Director’s New Innovator Award from the National Institute of Mental Health (1DP2MH11024701; J.E.P.-C.), a National Institute of Mental Health grant (1R011MH120269; J.E.P.-C.), a 4D Nucleome Common Fund grant (1U01HL12999801; J.E.P.-C), a joint NSF–NIGMS grant to support research at the interface of the biological and mathematical sciences (1562665; J.E.P.-C.), a Brain Research Foundation Fay Frank Seed Grant (J.E.P.-C.) and a National Science Foundation Graduate Research Fellowship under grant DGE-1321851 (J.A.B.).

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J.E.P.-C. and J.A.B. wrote the paper.

Correspondence to Jennifer E. Phillips-Cremins.

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Beagan, J.A., Phillips-Cremins, J.E. On the existence and functionality of topologically associating domains. Nat Genet 52, 8–16 (2020). https://doi.org/10.1038/s41588-019-0561-1

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