A high-resolution map of transcriptional repression.
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.
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.
Ziwei
Z
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
KE
Brown
Epigenetics Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom.
Thomas
T
Carroll
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.
Benjamin
0000-0001-6101-3786
B
Taylor
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
IF
Vidal
Wellcome Trust - Medical Research Council Stem Cell Institute, Cambridge, United Kingdom.|Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Brian
0000-0002-0231-3073
B
Hendrich
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.
David
D
Rueda
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.
Amanda G
AG
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.|Integrative Biology Section, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom.
Matthias
0000-0003-2889-3288
M
Merkenschlager
D000818:Animals; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000378:metabolism; D015536:Down-Regulation; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism; D051740:Ikaros Transcription Factor / Q000378:metabolism; D051379:Mice; D054448:Precursor Cells, B-Lymphoid / Q000502:physiology; D012319:RNA Polymerase II / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D012319:RNA Polymerase II; D006655:Histone Deacetylases; C509277:Mi-2beta protein, mouse; D004265:DNA Helicases
B cell; Ikaros; chromosomes; corepressor complex; gene silencing; genes; mouse; transcriptional repression