Differential regulation of OCT4 targets facilitates reacquisition of pluripotency

Sudhir Thakurela, Camille Sindhu, Evgeny Yurkovsky, Christina Riemenschneider, Zachary D. Smith, Iftach Nachman () and Alexander Meissner ()
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Sudhir Thakurela: Harvard University
Camille Sindhu: Harvard University
Evgeny Yurkovsky: Tel Aviv University
Christina Riemenschneider: Max Planck Institute for Molecular Genetics
Zachary D. Smith: Harvard University
Iftach Nachman: Tel Aviv University
Alexander Meissner: Harvard University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Ectopic transcription factor expression enables reprogramming of somatic cells to pluripotency, albeit with generally low efficiency. Despite steady progress in the field, the exact molecular mechanisms that coordinate this remarkable transition still remain largely elusive. To better characterize the final steps of pluripotency induction, we optimized an experimental system where pluripotent stem cells are differentiated for set intervals before being reintroduced to pluripotency-supporting conditions. Using this approach, we identify a transient period of high-efficiency reprogramming where ectopic transcription factors, but not serum/LIF alone, rapidly revert cells to pluripotency with near 100% efficiency. After this period, cells reprogram with somatic-like kinetics and efficiencies. We identify a set of OCT4 bound cis-regulatory elements that are dynamically regulated during this transient phase and appear central to facilitating reprogramming. Interestingly, these regions remain hypomethylated during in vitro and in vivo differentiation, which may allow them to act as primary targets of ectopically induced factors during somatic cell reprogramming.

Date: 2019
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DOI: 10.1038/s41467-019-11741-5

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