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.
Highlights
Poised enhancers (PEs) represent a genetically distinct set of distal regulatory elements that control the expression of major developmental genes
We previously found that PEs have a unique and modular genetic composition[5,9], since compared to other enhancer classes, they are frequently located close to orphan CGI (oCGI) (i.e. 70–80% of PEs are located within 3 kb of computationally defined “weak” CGIs5 or biochemically defined CGIs9, known as Non-Methylated Islands (NMI)22)
Our previous work suggested that PEs could play essential roles during the induction of major developmental genes once pluripotent cells start differentiating[5]
Summary
Poised enhancers (PEs) represent a genetically distinct set of distal regulatory elements that control the expression of major developmental genes. Poised enhancers (PEs) were originally described in ESC1,2 as a rather limited set of distal regulatory elements that, before becoming activated upon cellular differentiation, are already bookmarked in pluripotent cells with unique chromatin and topological features. We showed that the unique epigenetic, topological, and regulatory properties of PEs are genetically encoded and critically dependent on the presence of CpG islands (CGIs) that are not associated with annotated promoters and that are referred to as orphan CGI (oCGI)[6,7,8,9] This led us to suggest that the genetic, epigenetic, and topological features of PEs could endow developmental loci with a permissive regulatory landscape that facilitates the precise and specific induction of PE–target genes upon pluripotent cell differentiation[5,9]. By deleting conserved PEs in mouse and chicken embryos, we conclusively demonstrate that this type of regulatory elements is essential for the proper expression of major developmental genes during vertebrate embryogenesis
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