Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells

• Published in: Nature (London) Vol. 530; no. 7588; pp. 113 - 116
• Main Authors: de Dieuleveult, Maud, Yen, Kuangyu, Hmitou, Isabelle, Depaux, Arnaud, Boussouar, Fayçal, Dargham, Daria Bou, Jounier, Sylvie, Humbertclaude, Hélène, Ribierre, Florence, Baulard, Céline, Farrell, Nina P., Park, Bongsoo, Keime, Céline, Carrière, Lucie, Berlivet, Soizick, Gut, Marta, Gut, Ivo, Werner, Michel, Deleuze, Jean-François, Olaso, Robert, Aude, Jean-Christophe, Chantalat, Sophie, Pugh, B. Franklin, Gérard, Matthieu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2016; Nature Publishing Group
• Subjects: 631/208/177; 631/337/100/102; Animals; Cells; Chromatin; Chromatin Assembly and Disassembly; Deoxyribonucleic acid; DNA; DNA Helicases - metabolism; DNA-Binding Proteins - metabolism; Embryonic stem cells; Embryos; Gene expression; Gene Expression Regulation; Genetic aspects; Genome - genetics; Genome-wide association studies; Genomes; Histones - metabolism; Humanities and Social Sciences; letter; Life Sciences; Mice; Micrococcal Nuclease - metabolism; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; multidisciplinary; Nuclear Proteins - metabolism; Nucleosomes - genetics; Nucleosomes - metabolism; Promoter Regions, Genetic - genetics; RNA polymerase; RNA Polymerase II - metabolism; Science; Substrate Specificity; Trans-Activators - metabolism; Transcription Factors - metabolism; Transcription Initiation Site
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature16505

Genome-wide binding profiles for eight different chromatin remodellers in mouse embryonic stem (ES) cells are determined at single nucleosome resolution; each remodeller binds at specific nucleosome positions relative to the start of genes, and the same remodeller acts as a positive or negative regulator of transcription depending on the promoter chromatin organization and epigenetic marking of the gene it binds. Chromatin remodellers in stem cells The action of chromatin remodeling enzymes is required to allow transcription factors and the general transcription machinery access to DNA. Matthieu Gérard and colleagues determine genome-wide binding profiles for eight different chromatin remodellers in mouse embryonic stem cells at single nucleosome resolution. They find that each remodeller binds at specific nucleosome positions relative to the start of genes, and the same remodeller can act as a positive or negative regulator of transcription depending on the activity of the gene it binds. The findings illustrate how remodellers work together at specific nucleosome positions adjacent to nucleosome-depleted promoter regions in order to regulate transcription. ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers 1 , 2 , 3 target specific nucleosomes to regulate transcription is unclear. Here we present genome-wide remodeller–nucleosome interaction profiles for the chromatin remodellers Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank micrococcal nuclease (MNase)-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription. Surprisingly, large CpG-rich NFRs that extend downstream of annotated transcriptional start sites are nevertheless bound by non-nucleosomal or subnucleosomal histone variants (H3.3 and H2A.Z) and marked by H3K4me3 and H3K27ac modifications. RNA polymerase II therefore navigates hundreds of base pairs of altered chromatin in the sense direction before encountering an MNase-resistant nucleosome at the 3′ end of the NFR. Transcriptome analysis after remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. Whereas at active genes individual remodellers have either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner. These findings indicate that remodellers target specific nucleosomes at the edge of NFRs, where they regulate ES cell transcriptional programs.