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      Dual functionality of cis-regulatory elements as developmental enhancers and Polycomb response elements

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          Abstract

          Here, Erceg et al. studied the occupancy of the Drosophila PhoRC during embryogenesis and revealed extensive co-occupancy at developmental enhancers. By using an established in vivo assay for Polycomb response element (PRE) activity, they show that a subset of characterized developmental enhancers can function as PREs and silence transcription in a Polycomb-dependent manner, thereby suggesting that reuse of the same elements by the PcG system may help fine-tune gene expression and ensure the timely maintenance of cell identities.

          Abstract

          Developmental gene expression is tightly regulated through enhancer elements, which initiate dynamic spatio–temporal expression, and Polycomb response elements (PREs), which maintain stable gene silencing. These two cis-regulatory functions are thought to operate through distinct dedicated elements. By examining the occupancy of the Drosophila pleiohomeotic repressive complex (PhoRC) during embryogenesis, we revealed extensive co-occupancy at developmental enhancers. Using an established in vivo assay for PRE activity, we demonstrated that a subset of characterized developmental enhancers can function as PREs, silencing transcription in a Polycomb-dependent manner. Conversely, some classic Drosophila PREs can function as developmental enhancers in vivo, activating spatio–temporal expression. This study therefore uncovers elements with dual function: activating transcription in some cells (enhancers) while stably maintaining transcriptional silencing in others (PREs). Given that enhancers initiate spatio–temporal gene expression, reuse of the same elements by the Polycomb group (PcG) system may help fine-tune gene expression and ensure the timely maintenance of cell identities.

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          A unique chromatin signature uncovers early developmental enhancers in humans.

          Cell-fate transitions involve the integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of genomic sequences that control human embryonic development represents a formidable challenge. Here we show that in human embryonic stem cells (hESCs), unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, monomethylation of histone H3 at lysine 4 (H3K4me1), and low nucleosomal density. In addition, elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized hESC enhancers, and are located proximally to genes expressed in hESCs and the epiblast. In contrast, elements of the second class, which we term 'poised enhancers', are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3), and are linked to genes inactive in hESCs and instead are involved in orchestrating early steps in embryogenesis, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of poised enhancers acquires a chromatin signature associated with active enhancers. When assayed in zebrafish embryos, poised enhancers are able to direct cell-type and stage-specific expression characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that early developmental enhancers are epigenetically pre-marked in hESCs and indicate an unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the wealth of new regulatory sequences identified here provides an invaluable resource for studies and isolation of transient, rare cell populations representing early stages of human embryogenesis.
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            Transcription factors: from enhancer binding to developmental control.

            Developmental progression is driven by specific spatiotemporal domains of gene expression, which give rise to stereotypically patterned embryos even in the presence of environmental and genetic variation. Views of how transcription factors regulate gene expression are changing owing to recent genome-wide studies of transcription factor binding and RNA expression. Such studies reveal patterns that, at first glance, seem to contrast with the robustness of the developmental processes they encode. Here, we review our current knowledge of transcription factor function from genomic and genetic studies and discuss how different strategies, including extensive cooperative regulation (both direct and indirect), progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development.
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              Histone H3K27ac separates active from poised enhancers and predicts developmental state.

              Developmental programs are controlled by transcription factors and chromatin regulators, which maintain specific gene expression programs through epigenetic modification of the genome. These regulatory events at enhancers contribute to the specific gene expression programs that determine cell state and the potential for differentiation into new cell types. Although enhancer elements are known to be associated with certain histone modifications and transcription factors, the relationship of these modifications to gene expression and developmental state has not been clearly defined. Here we interrogate the epigenetic landscape of enhancer elements in embryonic stem cells and several adult tissues in the mouse. We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements containing H3K4me1 alone. This indicates that the amount of actively used enhancers is lower than previously anticipated. Furthermore, poised enhancer networks provide clues to unrealized developmental programs. Finally, we show that enhancers are reset during nuclear reprogramming.
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                Author and article information

                Journal
                Genes Dev
                Genes Dev
                genesdev
                genesdev
                GAD
                Genes & Development
                Cold Spring Harbor Laboratory Press
                0890-9369
                1549-5477
                15 March 2017
                15 March 2017
                : 31
                : 6
                : 590-602
                Affiliations
                [1 ]Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg D69117, Germany;
                [2 ]Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland
                Author notes
                [3]

                Present address: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

                [4]

                These authors contributed equally to this work.

                Corresponding author: furlong@ 123456embl.de
                Author information
                http://orcid.org/0000-0002-9544-8339
                Article
                8711660
                10.1101/gad.292870.116
                5393054
                28381411
                fc99c270-0c21-48ef-9a9c-f708288e77ef
                © 2017 Erceg et al.; Published by Cold Spring Harbor Laboratory Press

                This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.

                History
                : 28 October 2016
                : 3 March 2017
                Page count
                Pages: 13
                Funding
                Funded by: Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659
                Award ID: FU 750/1-2
                Funded by: Louis-Jeantet Foundation http://dx.doi.org/10.13039/501100001706
                Categories
                Research Paper

                polycomb response elements (pres),pleiohomeotic repressive complex (phorc),developmental enhancers,spatio–temporal expression,transcriptional repression,silencing,embryonic development

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