Zeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells

Chiara Cencioni (), Francesco Spallotta, Matteo Savoia, Carsten Kuenne, Stefan Guenther, Agnese Re, Susanne Wingert, Maike Rehage, Duran Sürün, Mauro Siragusa, Jacob G. Smith, Frank Schnütgen, Harald von Melchner, Michael A. Rieger, Fabio Martelli, Antonella Riccio, Ingrid Fleming, Thomas Braun, Andreas M. Zeiher, Antonella Farsetti () and Carlo Gaetano ()
Additional contact information
Chiara Cencioni: Goethe University
Francesco Spallotta: Goethe University
Matteo Savoia: Goethe University
Carsten Kuenne: Max Planck Institute for Heart and Lung Research
Stefan Guenther: Max Planck Institute for Heart and Lung Research
Agnese Re: Institute of Cell Biology and Neurobiology (IBCN)
Susanne Wingert: Goethe University
Maike Rehage: Goethe University
Duran Sürün: Goethe University
Mauro Siragusa: Goethe University
Jacob G. Smith: University College London
Frank Schnütgen: Goethe University
Harald von Melchner: Goethe University
Michael A. Rieger: Goethe University
Fabio Martelli: IRCCS-Policlinico San Donato
Antonella Riccio: University College London
Ingrid Fleming: Goethe University
Thomas Braun: Max-Planck-Institute for Heart and Lung Research
Andreas M. Zeiher: Goethe University
Antonella Farsetti: Institute of Cell Biology and Neurobiology (IBCN)
Carlo Gaetano: Goethe University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Nitric oxide (NO) synthesis is a late event during differentiation of mouse embryonic stem cells (mESC) and occurs after release from serum and leukemia inhibitory factor (LIF). Here we show that after release from pluripotency, a subpopulation of mESC, kept in the naive state by 2i/LIF, expresses endothelial nitric oxide synthase (eNOS) and endogenously synthesizes NO. This eNOS/NO-positive subpopulation (ESNO+) expresses mesendodermal markers and is more efficient in the generation of cardiovascular precursors than eNOS/NO-negative cells. Mechanistically, production of endogenous NO triggers rapid Hdac2 S-nitrosylation, which reduces association of Hdac2 with the transcriptional repression factor Zeb1, allowing mesendodermal gene expression. In conclusion, our results suggest that the interaction between Zeb1, Hdac2, and eNOS is required for early mesendodermal differentiation of naive mESC.

Date: 2018
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DOI: 10.1038/s41467-018-03668-0

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