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Transcription factors and 3D genome conformation in cell-fate decisions


How cells adopt different identities has long fascinated biologists. Signal transduction in response to environmental cues results in the activation of transcription factors that determine the gene-expression program characteristic of each cell type. Technological advances in the study of 3D chromatin folding are bringing the role of genome conformation in transcriptional regulation to the fore. Characterizing this role of genome architecture has profound implications, not only for differentiation and development but also for diseases including developmental malformations and cancer. Here we review recent studies indicating that the interplay between transcription and genome conformation is a driving force for cell-fate decisions.

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We apologize to the authors of many relevant studies for not citing their work owing to space limitations. We thank members of the Stadhouders, Filion and Graf laboratories for helpful discussions. G.F. and T.G. are supported by the European Research Council under the 7th Framework Programme FP7/2007-2013 (ERC Synergy Grant 4D-Genome, grant agreement 609989). R.S. is supported by the Netherlands Organization for Scientific Research (VENI 91617114) and an Erasmus MC Fellowship.

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Nature thanks Peter Fraser, Konrad Hochedlinger and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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R.S. and T.G. conceived and wrote the manuscript with essential input from G.J.F. Figures were prepared by R.S.

Competing interests

The authors declare no competing interests.

Correspondence to Ralph Stadhouders or Thomas Graf.

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Fig. 1: Cell identity as a transcription-factor-driven emergent property.
Fig. 2: Three-dimensional folding principles of chromatin.
Fig. 3: Compartmentalization and loop extrusion shape genome conformation.
Fig. 4: Scenarios and examples of how genome conformation helps to shape cell identity.


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