Regulation of Myc transcription by an enhancer cluster dedicated to pluripotency and early embryonic expression

Lin Li-Bao, Covadonga Díaz-Díaz, Morena Raiola, Rocío Sierra, Susana Temiño, Francisco J. Moya, Sandra Rodriguez-Perales, Elisa Santos, Giovanna Giovinazzo, Tore Bleckwehl, Álvaro Rada-Iglesias, Francois Spitz and Miguel Torres ()
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Lin Li-Bao: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Covadonga Díaz-Díaz: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Morena Raiola: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Rocío Sierra: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Susana Temiño: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Francisco J. Moya: Centro Nacional de Investigaciones Oncológicas (CNIO)
Sandra Rodriguez-Perales: Centro Nacional de Investigaciones Oncológicas (CNIO)
Elisa Santos: CNIC
Giovanna Giovinazzo: Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)
Tore Bleckwehl: University of Cologne
Álvaro Rada-Iglesias: CSIC/University of Cantabria
Francois Spitz: The University of Chicago
Miguel Torres: Centro Nacional de Investigaciones Cardiovasculares (CNIC)

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract MYC plays various roles in pluripotent stem cells, including the promotion of somatic cell reprogramming to pluripotency, the regulation of cell competition and the control of embryonic diapause. However, how Myc expression is regulated in this context remains unknown. The Myc gene lies within a ~ 3-megabase gene desert with multiple cis-regulatory elements. Here we use genomic rearrangements, transgenesis and targeted mutation to analyse Myc regulation in early mouse embryos and pluripotent stem cells. We identify a topologically-associated region that homes enhancers dedicated to Myc transcriptional regulation in stem cells of the pre-implantation and early post-implantation embryo. Within this region, we identify elements exclusively dedicated to Myc regulation in pluripotent cells, with distinct enhancers that sequentially activate during naive and formative pluripotency. Deletion of pluripotency-specific enhancers dampens embryonic stem cell competitive ability. These results identify a topologically defined enhancer cluster dedicated to early embryonic expression and uncover a modular mechanism for the regulation of Myc expression in different states of pluripotency.

Date: 2024
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DOI: 10.1038/s41467-024-48258-5

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