The Fgf/Erf/NCoR1/2 repressive axis controls trophoblast cell fate

Andreas Lackner, Michael Müller, Magdalena Gamperl, Delyana Stoeva, Olivia Langmann, Henrieta Papuchova, Elisabeth Roitinger, Gerhard Dürnberger, Richard Imre, Karl Mechtler and Paulina A. Latos ()
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Andreas Lackner: Medical University of Vienna
Michael Müller: Medical University of Vienna
Magdalena Gamperl: Medical University of Vienna
Delyana Stoeva: Medical University of Vienna
Olivia Langmann: Medical University of Vienna
Henrieta Papuchova: Medical University of Vienna
Elisabeth Roitinger: Institute of Molecular Pathology
Gerhard Dürnberger: Institute of Molecular Pathology
Richard Imre: Institute of Molecular Pathology
Karl Mechtler: Institute of Molecular Pathology
Paulina A. Latos: Medical University of Vienna

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Placental development relies on coordinated cell fate decisions governed by signalling inputs. However, little is known about how signalling cues are transformed into repressive mechanisms triggering lineage-specific transcriptional signatures. Here, we demonstrate that upon inhibition of the Fgf/Erk pathway in mouse trophoblast stem cells (TSCs), the Ets2 repressor factor (Erf) interacts with the Nuclear Receptor Co-Repressor Complex 1 and 2 (NCoR1/2) and recruits it to key trophoblast genes. Genetic ablation of Erf or Tbl1x (a component of the NCoR1/2 complex) abrogates the Erf/NCoR1/2 interaction. This leads to mis-expression of Erf/NCoR1/2 target genes, resulting in a TSC differentiation defect. Mechanistically, Erf regulates expression of these genes by recruiting the NCoR1/2 complex and decommissioning their H3K27ac-dependent enhancers. Our findings uncover how the Fgf/Erf/NCoR1/2 repressive axis governs cell fate and placental development, providing a paradigm for Fgf-mediated transcriptional control.

Date: 2023
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DOI: 10.1038/s41467-023-38101-8

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