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      Repressive Chromatin in Caenorhabditis elegans: Establishment, Composition, and Function

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          Abstract

          Chromatin is organized and compacted in the nucleus through the association of histones and other proteins, which together control genomic activity. Two broad types of chromatin can be distinguished: euchromatin, which is generally transcriptionally active, and heterochromatin, which is repressed. Here we examine the current state of our understanding of repressed chromatin in Caenorhabditis elegans, focusing on roles of histone modifications associated with repression, such as methylation of histone H3 lysine 9 (H3K9me2/3) or the Polycomb Repressive Complex 2 ( MES-2/3/6)-deposited modification H3K27me3, and on proteins that recognize these modifications. Proteins involved in chromatin repression are important for development, and have demonstrated roles in nuclear organization, repetitive element silencing, genome integrity, and the regulation of euchromatin. Additionally, chromatin factors participate in repression with small RNA pathways. Recent findings shed light on heterochromatin function and regulation in C. elegans, and should inform our understanding of repressed chromatin in other animals.

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          Most cited references114

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          Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project.

          We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor-binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor-binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.
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            UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.

            The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates. The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3). Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells. The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem-cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.
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              How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers.

              Histones comprise the major protein component of chromatin, the scaffold in which the eukaryotic genome is packaged, and are subject to many types of post-translational modifications (PTMs), especially on their flexible tails. These modifications may constitute a 'histone code' and could be used to manage epigenetic information that helps extend the genetic message beyond DNA sequences. This proposed code, read in part by histone PTM-binding 'effector' modules and their associated complexes, is predicted to define unique functional states of chromatin and/or regulate various chromatin-templated processes. A wealth of structural and functional data show how chromatin effector modules target their cognate covalent histone modifications. Here we summarize key features in molecular recognition of histone PTMs by a diverse family of 'reader pockets', highlighting specific readout mechanisms for individual marks, common themes and insights into the downstream functional consequences of the interactions. Changes in these interactions may have far-reaching implications for human biology and disease, notably cancer.
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                Author and article information

                Journal
                Genetics
                Genetics
                genetics
                genetics
                genetics
                Genetics
                Genetics Society of America
                0016-6731
                1943-2631
                February 2018
                25 February 2018
                25 February 2018
                : 208
                : 2
                : 491-511
                Affiliations
                [* ]The Gurdon Institute, University of Cambridge CB2 1QN, United Kingdom
                []Department of Genetics, University of Cambridge CB2 1QN, United Kingdom
                []Friedrich Miescher Institute for Biomedical Research (FMI), 4058 Basel, Switzerland, and
                [§ ]Faculty of Natural Sciences, University of Basel, 4056, Switzerland
                Author notes
                [1 ]Corresponding authors: The Gurdon Institute and Department of Genetics, University of Cambridge, Cambridge, United Kingdom CB2 1QN. E-mail: j.ahringer@ 123456gurdon.cam.ac.uk ; and Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland. E-mail: susan.gasser@ 123456fmi.ch
                Author information
                http://orcid.org/0000-0002-7074-4051
                http://orcid.org/0000-0003-3610-9123
                Article
                300386
                10.1534/genetics.117.300386
                5788517
                29378810
                a96b6afe-046c-42f1-8128-4e36a0935135
                Copyright © 2018 by the Genetics Society of America

                Available freely online through the author-supported open access option.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 October 2017
                : 18 November 2017
                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 154, Pages: 21
                Categories
                WormBook
                Gene and Genome Regulatory Mechanisms

                Genetics
                c. elegans,chromatin,heterochromatin,histone methylation,h3k9me,h3k27me,wormbook
                Genetics
                c. elegans, chromatin, heterochromatin, histone methylation, h3k9me, h3k27me, wormbook

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