A transcribed enhancer dictates mesendoderm specification in pluripotency

Michael Alexanian, Daniel Maric, Stephen P. Jenkinson, Marco Mina, Clayton E. Friedman, Ching-Chia Ting, Rudi Micheletti, Isabelle Plaisance, Mohamed Nemir, Damien Maison, Jasmin Kernen, Iole Pezzuto, Dominic Villeneuve, Frédéric Burdet, Mark Ibberson, Stephen L. Leib, Nathan J. Palpant, Nouria Hernandez, Samir Ounzain () and Thierry Pedrazzini ()
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Michael Alexanian: University of Lausanne Medical School
Daniel Maric: University of Lausanne Medical School
Stephen P. Jenkinson: University of Bern
Marco Mina: University of Lausanne
Clayton E. Friedman: University of Queensland
Ching-Chia Ting: University of Lausanne Medical School
Rudi Micheletti: University of Lausanne Medical School
Isabelle Plaisance: University of Lausanne Medical School
Mohamed Nemir: University of Lausanne Medical School
Damien Maison: University of Lausanne Medical School
Jasmin Kernen: University of Bern
Iole Pezzuto: University of Lausanne Medical School
Dominic Villeneuve: University of Lausanne
Frédéric Burdet: Swiss Institute of Bioinformatics
Mark Ibberson: Swiss Institute of Bioinformatics
Stephen L. Leib: University of Bern
Nathan J. Palpant: University of Queensland
Nouria Hernandez: University of Lausanne
Samir Ounzain: University of Lausanne Medical School
Thierry Pedrazzini: University of Lausanne Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: Abstract Enhancers and long noncoding RNAs (lncRNAs) are key determinants of lineage specification during development. Here, we evaluate remodeling of the enhancer landscape and modulation of the lncRNA transcriptome during mesendoderm specification. We sort mesendodermal progenitors from differentiating embryonic stem cells (ESCs) according to Eomes expression, and find that enhancer usage is coordinated with mesendoderm-specific expression of key lineage-determining transcription factors. Many of these enhancers are associated with the expression of lncRNAs. Examination of ESC-specific enhancers interacting in three-dimensional space with mesendoderm-specifying transcription factor loci identifies MesEndoderm Transcriptional Enhancer Organizing Region (Meteor). Genetic and epigenetic manipulation of the Meteor enhancer reveal its indispensable role during mesendoderm specification and subsequent cardiogenic differentiation via transcription-independent and -dependent mechanisms. Interestingly, Meteor-deleted ESCs are epigenetically redirected towards neuroectodermal lineages. Loci, topologically associating a transcribed enhancer and its cognate protein coding gene, appear to represent therefore a class of genomic elements controlling developmental competence in pluripotency.

Date: 2017
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DOI: 10.1038/s41467-017-01804-w

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