Retinoic Acid Induces Embryonic Stem Cells (ESCs) Transition to 2 Cell-Like State Through a Coordinated Expression of Dux and Duxbl1

Daniela Tagliaferri; Pellegrino Mazzone; Teresa M R Noviello; Martina Addeo; Tiziana Angrisano; Luigi Del Vecchio; Feliciano Visconte; Vitalba Ruggieri; Sabino Russi; Antonella Caivano; Irene Cantone; Mario De Felice; Michele Ceccarelli; Luigi Cerulo; Geppino Falco

doi:10.3389/fcell.2019.00385

Retinoic Acid Induces Embryonic Stem Cells (ESCs) Transition to 2 Cell-Like State Through a Coordinated Expression of Dux and Duxbl1

Front Cell Dev Biol. 2020 Jan 17:7:385. doi: 10.3389/fcell.2019.00385. eCollection 2019.

Authors

Daniela Tagliaferri¹, Pellegrino Mazzone¹, Teresa M R Noviello^{1

2}, Martina Addeo^{1

3}, Tiziana Angrisano³, Luigi Del Vecchio^{4

5}, Feliciano Visconte⁵, Vitalba Ruggieri⁶, Sabino Russi⁶, Antonella Caivano⁶, Irene Cantone⁴, Mario De Felice^{4

7}, Michele Ceccarelli^{1

2}, Luigi Cerulo^{1

2}, Geppino Falco^{1

2

6

7}

Affiliations

¹ Biogem Scarl, Istituto di Ricerche Genetiche "Gaetano Salvatore," Ariano Irpino, Italy.
² Department of Science and Technology, University of Sannio, Benevento, Italy.
³ Department of Biology, University of Naples Federico II, Naples, Italy.
⁴ Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.
⁵ CEINGE Biotecnologie Avanzate s.c.ar.l., Naples, Italy.
⁶ IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
⁷ Institute of Experimental Endocrinology and Oncology (IEOS), CNR, Naples, Italy.

Abstract

Embryonic stem cells (ESCs) are derived from inner cell mass (ICM) of the blastocyst. In serum/LIF culture condition, they show variable expression of pluripotency genes that mark cell fluctuation between pluripotency and differentiation metastate. The ESCs subpopulation marked by zygotic genome activation gene (ZGA) signature, including Zscan4, retains a wider differentiation potency than epiblast-derived ESCs. We have recently shown that retinoic acid (RA) significantly enhances Zscan4 cell population. However, it remains unexplored how RA initiates the ESCs to 2-cell like reprogramming. Here we found that RA is decisive for ESCs to 2C-like cell transition, and reconstructed the gene network surrounding Zscan4. We revealed that RA regulates 2C-like population co-activating Dux and Duxbl1. We provided novel evidence that RA dependent ESCs to 2C-like cell transition is regulated by Dux, and antagonized by Duxbl1. Our suggested mechanism could shed light on the role of RA on ESC reprogramming.

Keywords: 2-cell like; ESCs; metastate; pluripotency; retinoic acid.