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      The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression

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          Summary

          Chromatin remodeling complexes play essential roles in metazoan development through widespread control of gene expression, but the precise molecular mechanisms by which they do this in vivo remain ill defined. Using an inducible system with fine temporal resolution, we show that the nucleosome remodeling and deacetylation (NuRD) complex controls chromatin architecture and the protein binding repertoire at regulatory regions during cell state transitions. This is primarily exerted through its nucleosome remodeling activity while deacetylation at H3K27 follows changes in gene expression. Additionally, NuRD activity influences association of RNA polymerase II at transcription start sites and subsequent nascent transcript production, thereby guiding the establishment of lineage-appropriate transcriptional programs. These findings provide a detailed molecular picture of genome-wide modulation of lineage-specific transcription by an essential chromatin remodeling complex as well as insight into the orchestration of molecular events involved in transcriptional transitions in vivo.

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          Highlights

          • NuRD increases nucleosome density, expelling TFs or inhibiting recruitment

          • NuRD displaces RNA Pol II from TSSs, reducing nascent transcription

          • Local gains in TF and Mediator occupancy can be indirect effects of NuRD activity

          • Resetting protein binding at regulatory elements can promote or suppress transcription

          Abstract

          Bornelöv et al. define how NuRD, an abundant chromatin remodeling complex, fine-tunes gene expression. NuRD controls nucleosome positioning across regulatory elements genome-wide, controlling access of DNA-binding proteins to enhancers and promoters. This resetting of the transcription factor repertoire at regulatory elements restricts expression from some loci and induces transcription at others.

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          Most cited references45

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          Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans.

          Recent years have witnessed a sea change in our understanding of transcription regulation: whereas traditional models focused solely on the events that brought RNA polymerase II (Pol II) to a gene promoter to initiate RNA synthesis, emerging evidence points to the pausing of Pol II during early elongation as a widespread regulatory mechanism in higher eukaryotes. Current data indicate that pausing is particularly enriched at genes in signal-responsive pathways. Here the evidence for pausing of Pol II from recent high-throughput studies will be discussed, as well as the potential interconnected functions of promoter-proximally paused Pol II.
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            Identification and characterization of a family of mammalian methyl-CpG binding proteins.

            Methylation at the DNA sequence 5'-CpG is required for mouse development. MeCP2 and MBD1 (formerly PCM1) are two known proteins that bind specifically to methylated DNA via a related amino acid motif and that can repress transcription. We describe here three novel human and mouse proteins (MBD2, MBD3, and MBD4) that contain the methyl-CpG binding domain. MBD2 and MBD4 bind specifically to methylated DNA in vitro. Expression of MBD2 and MBD4 tagged with green fluorescent protein in mouse cells shows that both proteins colocalize with foci of heavily methylated satellite DNA. Localization is disrupted in cells that have greatly reduced levels of CpG methylation. MBD3 does not bind methylated DNA in vivo or in vitro. MBD1, MBD2, MBD3, and MBD4 are expressed in somatic tissues, but MBD1 and MBD2 expression is reduced or absent in embryonic stem cells which are known to be deficient in MeCP1 activity. The data demonstrate that MBD2 and MBD4 bind specifically to methyl-CpG in vitro and in vivo and are therefore likely to be mediators of the biological consequences of the methylation signal.
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              NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities.

              ATP-dependent chromatin-remodeling complexes are known to facilitate transcriptional activation by opening chromatin structures. We report a novel human complex, named NURD, which contains not only ATP-dependent nucleosome disruption activity, but also histone deacetylase activity, which usually associates with transcriptional repression. The deacetylation is stimulated by ATP on nucleosomal templates, suggesting that nucleosome disruption aids the deacetylase to access its substrates. One subunit of NURD was identified as MTA1, a metastasis-associated protein with a region similar to the nuclear receptor core-pressor, N-CoR; and antibodies against NURD partially relieve transcriptional repression by thyroid hormone receptor. These results suggest that ATP-dependent chromatin remodeling can participate in transcriptional repression by assisting repressors in gaining access to chromatin.
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                Author and article information

                Contributors
                Journal
                Mol Cell
                Mol. Cell
                Molecular Cell
                Cell Press
                1097-2765
                1097-4164
                05 July 2018
                05 July 2018
                : 71
                : 1
                : 56-72.e4
                Affiliations
                [1 ]Wellcome-MRC Stem Cell Institute, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK
                [2 ]European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL), Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK
                [3 ]Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
                Author notes
                []Corresponding author bertone@ 123456stemcells.cam.ac.uk
                [∗∗ ]Corresponding author bdh24@ 123456cam.ac.uk
                [4]

                These authors contributed equally

                [5]

                Lead Contact

                Article
                S1097-2765(18)30445-3
                10.1016/j.molcel.2018.06.003
                6039721
                30008319
                368844f1-4e19-429c-97a2-09578d969260
                © 2018 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 April 2017
                : 20 March 2018
                : 31 May 2018
                Categories
                Article

                Molecular biology
                nurd,transcription,chromatin,mediator,rna polymerase ii,transcription factor,enhancer,embryonic stem cells

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