A high-resolution map of transcriptional repression
Ziwei Liang,
Karen E Brown,
Thomas Carroll,
Benjamin Taylor,
Isabel Ferreirós Vidal,
Brian Hendrich,
David Rueda,
Amanda G Fisher,
Matthias Merkenschlager
Affiliations
Ziwei Liang
Lymphocyte Development Group, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom; Epigenetics Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Karen E Brown
Lymphocyte Development Group, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom; Epigenetics Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Thomas Carroll
Epigenetics Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Lymphocyte Development Group, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom; Epigenetics Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Isabel Ferreirós Vidal
Lymphocyte Development Group, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom; Epigenetics Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Wellcome Trust – Medical Research Council Stem Cell Institute, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
David Rueda
Single Molecule Imaging Group, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom; Integrative Biology Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Amanda G Fisher
Lymphocyte Development Group, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom; Epigenetics Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Lymphocyte Development Group, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom; Epigenetics Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom; Integrative Biology Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
Turning genes on and off is essential for development and homeostasis, yet little is known about the sequence and causal role of chromatin state changes during the repression of active genes. This is surprising, as defective gene silencing underlies developmental abnormalities and disease. Here we delineate the sequence and functional contribution of transcriptional repression mechanisms at high temporal resolution. Inducible entry of the NuRD-interacting transcriptional regulator Ikaros into mouse pre-B cell nuclei triggered immediate binding to target gene promoters. Rapid RNAP2 eviction, transcriptional shutdown, nucleosome invasion, and reduced transcriptional activator binding required chromatin remodeling by NuRD-associated Mi2beta/CHD4, but were independent of HDAC activity. Histone deacetylation occurred after transcriptional repression. Nevertheless, HDAC activity contributed to stable gene silencing. Hence, high resolution mapping of transcriptional repression reveals complex and interdependent mechanisms that underpin rapid transitions between transcriptional states, and elucidates the temporal order, functional role and mechanistic separation of NuRD-associated enzymatic activities.
