Topic
SWI/SNF
About: SWI/SNF is a research topic. Over the lifetime, 1157 publications have been published within this topic receiving 88511 citations. The topic is also known as: SWI-SNF-type complex & BAF-type complex.
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TL;DR: This work isolated nucleosome-bound sequences at high resolution from yeast and used these sequences in a new computational approach to construct and validate experimentally a nucleosom–DNA interaction model, and to predict the genome-wide organization of nucleosomes.
Abstract: Eukaryotic genomes are packaged into nucleosome particles that occlude the DNA from interacting with most DNA binding proteins. Nucleosomes have higher affinity for particular DNA sequences, reflecting the ability of the sequence to bend sharply, as required by the nucleosome structure. However, it is not known whether these sequence preferences have a significant influence on nucleosome position in vivo, and thus regulate the access of other proteins to DNA. Here we isolated nucleosome-bound sequences at high resolution from yeast and used these sequences in a new computational approach to construct and validate experimentally a nucleosome–DNA interaction model, and to predict the genome-wide organization of nucleosomes. Our results demonstrate that genomes encode an intrinsic nucleosome organization and that this intrinsic organization can explain ∼50% of the in vivo nucleosome positions. This nucleosome positioning code may facilitate specific chromosome functions including transcription factor binding, transcription initiation, and even remodelling of the nucleosomes themselves. Eukaryotic genomes do not exist in vivo as naked DNA, but in complexes known as chromatin. Chromatin contains nucleosomes, short stretches of DNA tightly wrapped around a histone protein core, which exclude most DNA binding proteins and so act as repressors. A combined computational and experimental approach has been used to determine DNA sequence preferences of nucleosomes and to predict genome-wide nucleosome organization. The yeast genome encodes an intrinsic nucleosome organization that explains about half of the in vivo nucleosome positions. Highly conserved across eukaryotes, the code directs transcription factors to their binding sites and facilitates many other specific chromosome functions. An accompanying News and Views piece discusses the role of DNA sequence and other regulators in nucleosome positioning. The cover graphic represents a stretch of chromatin including several nucleosomes. A combined computational and experimental approach is used to determine the DNA sequence preferences of nucleosomes and predict genome-wide nucleosome organization. The yeast genome encodes an intrinsic nucleosome organization, which can explain about 50% of in vivo nucleosome positions.
1,376 citations
TL;DR: It is found that nucleosome phasing relative to the transcription start sites is directly correlated to RNA polymerase II (Pol II) binding and the first nucleosomes downstream of a start site exhibits differential positioning in active and silent genes.
1,354 citations
TL;DR: The results indicate that the intrinsic DNA sequence preferences of nucleosomes have a central role in determining the organization ofucleosomes in vivo.
Abstract: The nucleosomes are the basic repeating units of eukaryotic chromatin, and nucleosome organization is critically important for gene regulation. Kaplan et al. tested the importance of the intrinsic DNA sequence preferences of nucleosomes by measuring the genome-wide occupancy of nucleosomes assembled on purified yeast genomic DNA. The resulting map is remarkably similar to in vivo nucleosome maps, indicating that the organization of nucleosomes in vivo is largely governed by the underlying genomic DNA sequence. This study tests the importance of the intrinsic DNA sequence preferences of nucleosomes by measuring the genome-wide occupancy of nucleosomes assembled on purified yeast genomic DNA. The resulting map is similar to in vivo nucleosome maps, indicating that the organization of nucleosomes in vivo is largely governed by the underlying genomic DNA sequence. Nucleosome organization is critical for gene regulation1. In living cells this organization is determined by multiple factors, including the action of chromatin remodellers2, competition with site-specific DNA-binding proteins3, and the DNA sequence preferences of the nucleosomes themselves4,5,6,7,8. However, it has been difficult to estimate the relative importance of each of these mechanisms in vivo7,9,10,11, because in vivo nucleosome maps reflect the combined action of all influencing factors. Here we determine the importance of nucleosome DNA sequence preferences experimentally by measuring the genome-wide occupancy of nucleosomes assembled on purified yeast genomic DNA. The resulting map, in which nucleosome occupancy is governed only by the intrinsic sequence preferences of nucleosomes, is similar to in vivo nucleosome maps generated in three different growth conditions. In vitro, nucleosome depletion is evident at many transcription factor binding sites and around gene start and end sites, indicating that nucleosome depletion at these sites in vivo is partly encoded in the genome. We confirm these results with a micrococcal nuclease-independent experiment that measures the relative affinity of nucleosomes for ∼40,000 double-stranded 150-base-pair oligonucleotides. Using our in vitro data, we devise a computational model of nucleosome sequence preferences that is significantly correlated with in vivo nucleosome occupancy in Caenorhabditis elegans. Our results indicate that the intrinsic DNA sequence preferences of nucleosomes have a central role in determining the organization of nucleosomes in vivo.
1,205 citations
TL;DR: Recently, proteins that were initially identified as necessary for transcriptional regulation have been shown to alter nucleosomal structure and are likely to play a central role in appropriate regulation of eukaryotic genes.
Abstract: The nucleosome, which is the primary building block of chromatin, is not a static structure: It can adopt alternative conformations. Changes in solution conditions or changes in histone acetylation state cause nucleosomes and nucleosomal arrays to behave with altered biophysical properties. Distinct subpopulations of nucleosomes isolated from cells have chromatographic properties and nuclease sensitivity different from those of bulk nucleosomes. Recently, proteins that were initially identified as necessary for transcriptional regulation have been shown to alter nucleosomal structure. These proteins are found in three types of multiprotein complexes that can acetylate nucleosomes, deacetylate nucleosomes, or alter nucleosome structure in an ATP-dependent manner. The direct modification of nucleosome structure by these complexes is likely to play a central role in appropriate regulation of eukaryotic genes.
1,189 citations
TL;DR: The contributions of SWI/SNF mutations to cancer formation are discussed, their normal functions are examined and opportunities for novel therapeutic interventions for SWI /SNF-mutant cancers are discussed.
Abstract: SWI/SNF chromatin remodelling complexes use the energy of ATP hydrolysis to remodel nucleosomes and to modulate transcription. Growing evidence indicates that these complexes have a widespread role in tumour suppression, as inactivating mutations in several SWI/SNF subunits have recently been identified at a high frequency in a variety of cancers. However, the mechanisms by which mutations in these complexes drive tumorigenesis are unclear. In this Review we discuss the contributions of SWI/SNF mutations to cancer formation, examine their normal functions and discuss opportunities for novel therapeutic interventions for SWI/SNF-mutant cancers.
1,071 citations