Downloaded from http://cshperspectives.cshlp.org/ at ROSWELL PARK CANCER INST on April 29, 2014 - Published by Cold Spring Harbor Laboratory Press Nucleosome Remodeling and Epigenetics Peter B. Becker and Jerry L. Workman Cold Spring Harb Perspect Biol 2013; doi: 10.1101/cshperspect.a017905 Subject Collection Epigenetics Erasers of Histone Acetylation: The Histone Histone H3 Mutations in Pediatric Brain Tumors Deacetylase Enzymes Xiaoyang Liu, Troy A. McEachron, Jeremy Edward Seto and Minoru Yoshida Schwartzentruber, et al. Regulation of the X Chromosomes in Cellular Reprogramming Caenorhabditis elegans Kazutoshi Takahashi Susan Strome, William G. Kelly, Sevinc Ercan, et al. Genomic Imprinting in Mammals A Brief History of Epigenetics Denise P. Barlow and Marisa S. Bartolomei Gary Felsenfeld The Discovery of Histone Demethylases Epigenetics of Ciliates Yujiang Geno Shi and Yu-ichi Tsukada Douglas L. Chalker, Eric Meyer and Kazufumi Mochizuki The Discovery of Histone Demethylases Nucleosome Remodeling and Epigenetics Yujiang Geno Shi and Yu-ichi Tsukada Peter B. Becker and Jerry L. Workman CpG Island Chromatin Is Shaped by Recruitment The Use of Mouse Models to Study Epigenetics of ZF-CxxC Proteins Marnie Blewitt and Emma Whitelaw Neil P. Blackledge, John P. Thomson and Peter J. Skene Neurospora crassa, a Model System for Epigenetics in Saccharomyces cerevisiae Epigenetics Research Michael Grunstein and Susan M. Gasser Rodolfo Aramayo and Eric U. Selker Plant Mobile Small RNAs Position-Effect Variegation, Heterochromatin Patrice Dunoyer, Charles Melnyk, Attila Molnar, et Formation, and Gene Silencing in Drosophila al. Sarah C.R. Elgin and Gunter Reuter For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/ Copyright © 2013 Cold Spring Harbor Laboratory Press; all rights reserved Downloaded from http://cshperspectives.cshlp.org/ at ROSWELL PARK CANCER INST on April 29, 2014 - Published by Cold Spring Harbor Laboratory Press Nucleosome Remodeling and Epigenetics Peter B. Becker1 and Jerry L. Workman2 1BioMedical Center, Ludwig-Maximilians-University, D-80336 Munich, Germany; 2Stowers Institute for Medical Research, Kansas City, Missouri 64110 Correspondence: [email protected]; [email protected] SUMMARY Eukaryotic chromatin is kept flexible and dynamic to respond to environmental, metabolic, and devel- opmental cues through the action of a family of so-called “nucleosome remodeling” ATPases. Consistent with their helicase ancestry, these enzymes experience conformation changes as they bind and hydrolyze ATP. At the same time they interact with DNA and histones, which alters histone–DNA interactions in target nucleosomes. Their action may lead to complete or partial disassembly of nucleosomes, the exchange of histones for variants, the assembly of nucleosomes, or the movement of histone octamers on DNA. “Remodeling” may render DNA sequences accessible to interacting proteins or, conversely, promote packing into tightly folded structures. Remodeling processes participate in every aspect of genome function. Remodeling activities are commonly integrated with other mechanisms such as histone modifications or RNA metabolism to assemble stable, epigenetic states. Outline 1 The discovery of nucleosome remodeling: 7 Regulation of remodelers by posttranslational A historical perspective modification 2 The nuts and bolts of nucleosome 8 Interaction of chromatin remodelers with remodeling DNA methylation 3 Diversity of nucleosome remodeling 9 Chromatin remodelers and histone variants complexes 10 Nucleosome remodeling during 4 Nucleosome remodeling factors as regulators development of transcription 11 Conclusions 5 Nucleosome remodeling in chromatin assembly and organization References 6 Recognition of histone modifications by chromatin remodelers Editors: C. David Allis, Marie-Laure Caparros, Thomas Jenuwein, and Danny Reinberg Additional Perspectives on Epigenetics available at www.cshperspectives.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a017905 Cite as Cold Spring Harb Perspect Biol 2013;5:a017905 1 Downloaded from http://cshperspectives.cshlp.org/ at ROSWELL PARK CANCER INST on April 29, 2014 - Published by Cold Spring Harbor Laboratory Press P.B. Becker and J.L. Workman OVERVIEW An unavoidable side effect of the organization of eukaryotic coupling to ATP hydrolysis. Like all biochemical reactions genomes into chromatin is the occlusion of DNA sequence by they are, in principle, reversible and the outcome of remod- histones and nonhistone chromatin components. Making use eling reactions—be it the disruption of histone–DNA interac- of the genetic information, be it as part of a developmental tions or their formation, the sliding of a histone octamer on or program or in response to environmental cues, for faithful off a particular DNA sequence, or alteration of the histone propagation of chromatin during replication or the repair of variant composition of a nucleosome—are largely deter- damage, necessitates that regulatory factors and complex ma- mined by the specification of remodeling enzymes and the chineries gain access to DNA sequence. The most fundamen- involvement of cofactors. tal issue of chromatin biology is, therefore, how to ensure Nucleosome remodeling ATPases are involved in each access to DNA despite the compact and protective chromatin and every aspect of genome utilization, be it the regulated organization. By its very nature, this organization generates a execution of developmental gene expression programs (Chio- default state of inaccessibility and, hence, inactivity of the da and Becker 2010; Ho and Crabtree 2010) or the fast tran- DNA that is subject to it. There are several reasons for this. scriptional response to environmental signals (Vicent et al. First, proteins cannot easilyassociate with DNA sequence that 2010). It also includes their involvement in the scheduled touches the nucleosomal histone surface. Second, nucleoso- replication of the genome (Falbo and Shen 2006; Neves-Costa mal DNA is strongly bent during its path around the histone and Varga-Weisz 2006; Morettini et al. 2008) or the surveil- octamer, and many DNA binding proteins find their target lance of the genome for DNA damage and its repair bya range sequence distorted and unrecognizable. Finally, nonhistone of strategies, including the recombination of chromosomal chromatin components may associate with nucleosomes segments (Altaf et al. 2007; Bao and Shen 2007; Downs bearing chemical modifications (i.e., histone posttranslation- et al. 2007). Defects in genes coding for nucleosome remod- al modifications) and fold the nucleosomal fiber into “higher- eling enzymes can have subtle or rather dramatic conse- order” structures that may be even less accessible. quences, depending on the processes affected and the The inevitable inaccessibility of DNA in chromatin may functional redundancy of the system. Failure of nucleosome appear as a problem at first sight, but evolution has turned it remodeling during development may compromise viability or into a strong asset by inventing enzymes that are able to “re- cause morphological defects (Chioda and Becker 2010; Ho model” nucleosomes. This allows access to DNA to be regu- and Crabtree 2010). In other cases, failure of remodeling sys- lated locally and differentially as needed. Nucleosome tems may render cells unable to cope with DNA damage and remodeling involves changing histone–DNA interactions as lead to genome instability and cancer (Cairns 2001; Weiss- a means of disrupting, assembling or moving nucleosomes. man and Knudsen 2009; Hargreaves and Crabtree 2011). Nucleosome remodeling enzymes may liberate segments of In this article we describe the discovery of nucleosome DNA by complete or partial disassembly of nucleosomes, remodelers through a combination of genetics and biochem- may alter the composition of nucleosomes with respect to istry, their mechanism of action, and the outcomes of remod- histone variants and, more indirectly, may also affect the fold- eling events. We outline the different families of remodeling ing of the nucleosomal fiber (Workman and Kingston 1998; enzymes, the protein domains that distinguish them, and the Kingston and Narlikar 1999; Becker and Horz 2002; Clapier diversity of complex machineries they reside in. We describe and Cairns 2009; Hargreaves and Crabtree 2011). the roles of remodelers in chromatin assembly, transcriptional Nucleosomes are rather stable entities attributable to the regulation, and development. Finally, we discuss the func- cumulative effect of many weak histone–DNA interactions tional crosstalk of nucleosome remodeling with histone vari- (Luger and Richmond 1998). It therefore comes as no surprise ants and posttranslational modifications of both histones and that nucleosome remodeling reactions require biochemical the remodelers themselves. 2 Cite as Cold Spring Harb Perspect Biol 2013;5:a017905 Downloaded from http://cshperspectives.cshlp.org/ at ROSWELL PARK CANCER INST on April 29, 2014 - Published by Cold Spring Harbor Laboratory Press Nucleosome Remodeling and Epigenetics 1 THE DISCOVERY OF NUCLEOSOME the inducer led to a fast closing of chromatin on dissocia- REMODELING: A HISTORICAL PERSPECTIVE tion of factors (Reik et al. 1991). These findings motivated the search for the active molecules and processes underly- Monitoring the differential accessibility of a complex ge- ing these transitions, which led to the identification of ATP- nome