The chromatin, topological and regulatory properties of pluripotency-associated poised enhancers are conserved in vivo

Giuliano Crispatzu (), Rizwan Rehimi, Tomas Pachano, Tore Bleckwehl, Sara Cruz-Molina, Cally Xiao, Esther Mahabir, Hisham Bazzi and Alvaro Rada-Iglesias ()
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Giuliano Crispatzu: Center for Molecular Medicine Cologne (CMMC), University of Cologne
Rizwan Rehimi: Center for Molecular Medicine Cologne (CMMC), University of Cologne
Tomas Pachano: Center for Molecular Medicine Cologne (CMMC), University of Cologne
Tore Bleckwehl: Center for Molecular Medicine Cologne (CMMC), University of Cologne
Sara Cruz-Molina: Max Planck Institute for Molecular Biomedicine
Cally Xiao: Center for Molecular Medicine Cologne (CMMC), University of Cologne
Esther Mahabir: Center for Molecular Medicine Cologne (CMMC), University of Cologne
Hisham Bazzi: Center for Molecular Medicine Cologne (CMMC), University of Cologne
Alvaro Rada-Iglesias: Center for Molecular Medicine Cologne (CMMC), University of Cologne

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Poised enhancers (PEs) represent a genetically distinct set of distal regulatory elements that control the expression of major developmental genes. Before becoming activated in differentiating cells, PEs are already bookmarked in pluripotent cells with unique chromatin and topological features that could contribute to their privileged regulatory properties. However, since PEs were originally characterized in embryonic stem cells (ESC), it is currently unknown whether PEs are functionally conserved in vivo. Here, we show that the chromatin and 3D structural features of PEs are conserved among mouse pluripotent cells both in vitro and in vivo. We also uncovered that the interactions between PEs and their target genes are globally controlled by the combined action of Polycomb, Trithorax and architectural proteins. Moreover, distal regulatory sequences located close to developmental genes and displaying the typical genetic (i.e. CpG islands) and chromatin (i.e. high accessibility and H3K27me3 levels) features of PEs are commonly found across vertebrates. These putative PEs show high sequence conservation within specific vertebrate clades, with only a few being evolutionary conserved across all vertebrates. Lastly, by genetically disrupting PEs in mouse and chicken embryos, we demonstrate that these regulatory elements play essential roles during the induction of major developmental genes in vivo.

Date: 2021
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DOI: 10.1038/s41467-021-24641-4

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