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      Causal role of histone acetylations in enhancer function

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      Taylor & Francis

      chromatin, enhancers, gene expression, histone acetylation, H3 globular domain

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          ABSTRACT

          Enhancers control development and cellular function by spatiotemporal regulation of gene expression. Co-occurrence of acetylation of histone H3 at lysine 27 (H3K27ac) and mono methylation of histone H3 at lysine 4 (H3K4me1) has been widely used for identification of active enhancers. However, increasing evidence suggests that using this combination of marks alone for enhancer identification gives an incomplete picture of the active enhancer repertoire. We have shown that the H3 globular domain acetylations, H3K64ac and H3K122ac, and an H4 tail acetylation, H4K16ac, are enriched at active enhancers together with H3K27ac, and also at a large number of enhancers without detectable H3K27ac. We propose that acetylations at these lysine residues of histones H3 and H4 might function by directly affecting chromatin structure, nucleosome–nucleosome interactions, nucleosome stability, and transcription factor accessibility.

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          Most cited references 54

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          Functions of DNA methylation: islands, start sites, gene bodies and beyond.

          DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first. Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.
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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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              Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression.

              Targeted gene regulation on a genome-wide scale is a powerful strategy for interrogating, perturbing, and engineering cellular systems. Here, we develop a method for controlling gene expression based on Cas9, an RNA-guided DNA endonuclease from a type II CRISPR system. We show that a catalytically dead Cas9 lacking endonuclease activity, when coexpressed with a guide RNA, generates a DNA recognition complex that can specifically interfere with transcriptional elongation, RNA polymerase binding, or transcription factor binding. This system, which we call CRISPR interference (CRISPRi), can efficiently repress expression of targeted genes in Escherichia coli, with no detectable off-target effects. CRISPRi can be used to repress multiple target genes simultaneously, and its effects are reversible. We also show evidence that the system can be adapted for gene repression in mammalian cells. This RNA-guided DNA recognition platform provides a simple approach for selectively perturbing gene expression on a genome-wide scale. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Transcription
                Transcription
                KTRN
                ktrn20
                Transcription
                Taylor & Francis
                2154-1264
                2154-1272
                2017
                28 October 2016
                28 October 2016
                : 8
                : 1
                : 40-47
                Affiliations
                School of biological sciences, University of Essex , Colchester, UK
                Author notes
                CONTACT Madapura M. Pradeepa pmadap@ 123456essex.ac.uk School of biological sciences, University of Essex, Wivenhoe Park , Colchester, CO43SQ, UK

                Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ktrn.

                1253529
                10.1080/21541264.2016.1253529
                5279748
                27792455
                © 2017 The Author(s). Published with license by Taylor & Francis

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

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                Figures: 1, Tables: 0, References: 58, Pages: 8
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                Molecular biology

                h3 globular domain, histone acetylation, gene expression, enhancers, chromatin

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