Dynamics of the 4D genome during in vivo lineage specification and differentiation

A. Marieke Oudelaar, Robert A. Beagrie, Matthew Gosden, Sara Ornellas, Emily Georgiades, Jon Kerry, Daniel Hidalgo, Joana Carrelha, Arun Shivalingam, Afaf H. El-Sagheer, Jelena M. Telenius, Tom Brown, Veronica J. Buckle, Merav Socolovsky, Douglas R. Higgs () and Jim R. Hughes ()
Additional contact information
A. Marieke Oudelaar: University of Oxford
Robert A. Beagrie: University of Oxford
Matthew Gosden: University of Oxford
Sara Ornellas: University of Oxford
Emily Georgiades: University of Oxford
Jon Kerry: University of Oxford
Daniel Hidalgo: University of Massachusetts Medical School Worcester
Joana Carrelha: University of Oxford
Arun Shivalingam: University of Oxford
Afaf H. El-Sagheer: University of Oxford
Jelena M. Telenius: University of Oxford
Tom Brown: University of Oxford
Veronica J. Buckle: University of Oxford
Merav Socolovsky: University of Massachusetts Medical School Worcester
Douglas R. Higgs: University of Oxford
Jim R. Hughes: University of Oxford

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Mammalian gene expression patterns are controlled by regulatory elements, which interact within topologically associating domains (TADs). The relationship between activation of regulatory elements, formation of structural chromatin interactions and gene expression during development is unclear. Here, we present Tiled-C, a low-input chromosome conformation capture (3C) technique. We use this approach to study chromatin architecture at high spatial and temporal resolution through in vivo mouse erythroid differentiation. Integrated analysis of chromatin accessibility and single-cell expression data shows that regulatory elements gradually become accessible within pre-existing TADs during early differentiation. This is followed by structural re-organization within the TAD and formation of specific contacts between enhancers and promoters. Our high-resolution data show that these enhancer-promoter interactions are not established prior to gene expression, but formed gradually during differentiation, concomitant with progressive upregulation of gene activity. Together, these results provide new insight into the close, interdependent relationship between chromatin architecture and gene regulation during development.

Date: 2020
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DOI: 10.1038/s41467-020-16598-7

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