Nucleosome positioning as a determinant of exon recognition

Tilgner, Hagen; Nikolaou, Christoforos; Althammer, Sonja; Sammeth, Michael; Beato, Miguel; Valcárcel, Juan; Guigó, Roderic

doi:10.1038/nsmb.1658

Cited by 405 publications

(445 citation statements)

References 52 publications

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“…Histone modifications such as H3K36me3, which we found positively correlated with resistant nucleosomes, are also thought to contribute to nucleosome stability and maintenance of transcription fidelity (Lieb and Clarke 2005;Lickwar et al 2009). Together, our measurements agree with an emerging picture of highly regulated nucleosome stability throughout the genome, which is likely critical for regulation of DNA templated events like transcription, splicing, and DNA replication (Tilgner et al 2009;Eaton et al 2010;Bintu et al 2011;Kwak et al 2013). …”

Section: Mnase-resistant Nucleosomes Tend To Be In Gene Bodies and Cosupporting

confidence: 75%

Nucleosome fragility is associated with future transcriptional response to developmental cues and stress in C. elegans

Jeffers

Lieb

2016

Genome Res.

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Nucleosomes have structural and regulatory functions in all eukaryotic DNA-templated processes. The position of nucleosomes on DNA and the stability of the underlying histone-DNA interactions affect the access of regulatory proteins to DNA. Both stability and position are regulated through DNA sequence, histone post-translational modifications, histone variants, chromatin remodelers, and transcription factors. Here, we explored the functional implications of nucleosome properties on gene expression and development in Caenorhabditis elegans embryos. We performed a time-course of micrococcal nuclease (MNase) digestion and measured the relative sensitivity or resistance of nucleosomes throughout the genome. Fragile nucleosomes were defined by nucleosomal DNA fragments that were recovered preferentially in early MNase-digestion time points. Nucleosome fragility was strongly and positively correlated with the AT content of the underlying DNA sequence. There was no correlation between promoter nucleosome fragility and the levels of histone modifications or histone variants. Genes with fragile nucleosomes in their promoters tended to be lowly expressed and expressed in a contextspecific way, operating in neuronal response, the immune system, and stress response. In addition to DNA-encoded nucleosome fragility, we also found fragile nucleosomes at locations where we expected to find destabilized nucleosomes, for example, at transcription factor binding sites where nucleosomes compete with DNA-binding factors. Our data suggest that in C. elegans promoters, nucleosome fragility is in large part DNA-encoded and that it poises genes for future context-specific activation in response to environmental stress and developmental cues.[Supplemental material is available for this article.]The fundamental unit of eukaryotic chromatin is the nucleosome, which consists of 147 bp of DNA wrapped around an octamer of histone proteins (Luger et al. 1997). Nucleosomes have important structural and regulatory functions in organizing the genome and restricting access of regulatory factors to the DNA sequence (Henikoff 2008). As such, the interactions between nucleosomes and DNA strongly influence the regulation of gene expression by determining DNA accessibility for transcription factors (TFs) and RNA polymerase. In addition to regulated nucleosome assembly and disassembly through the action of histone chaperones and chromatin remodelers, nucleosome stability is influenced by histone modifications, histone variants, DNA features encoded in cis, and competition with DNA-binding factors in trans . A complete picture of the mechanisms governing nucleosome stability is fundamental to understanding how gene expression is dynamically regulated.Nucleosome stability has been studied in vitro using sensitivity to enzymatic digestion or salt concentration (Bloom and Anderson 1978;Burton et al. 1978;Li et al. 1993;Polach and Widom 1995;Wu and Travers 2004;Jin and Felsenfeld 2007). Genome-wide adaptations of these methods have been used to identify nuc...

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Section: Mnase-resistant Nucleosomes Tend To Be In Gene Bodies and Cosupporting

confidence: 75%

Nucleosome fragility is associated with future transcriptional response to developmental cues and stress in C. elegans

Jeffers

Lieb

2016

Genome Res.

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“…Remarkably, the pattern of these alterations was not irregular, raising a question of the underlying mechanism. Apart from alterations of cross-exon protein interactions and/or RNA secondary/tertiary structure, chromatin and histone modifications have been recently shown to influence splicing [Andersson et al, 2009;Gama-Carvalho et al, 1997;Kolasinska-Zwierz et al, 2009;Kornblihtt et al, 2009;Schor et al, 2009;Tilgner et al, 2009]. Exon marking and nucleosome occupancy between exons and introns also show only ~1.5-fold differences and nucleosome occupancy improved exon recognition only to a limited degree [Spies et al, 2009].…”

Section: Discussionmentioning

confidence: 99%

Prediction of single‐nucleotide substitutions that result in exon skipping: identification of a splicing silencer inBRCA1exon 6

et al. 2011

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Missense, nonsense and translationally silent mtuations can inactivate genes by altering the inclusion of mutant exons in messenger RNA, but their overall fraction among disease-causing exonic substitutions is unknown. Here, we have systematically tested missense and silent mutations deposited in the BRCA1 mutation databases of unclassified variants for their effects on exon inclusion in the mRNA experimentally. The introduction of 21 BRCA1 variants in two minigene systems revealed a single example of

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“…4A). Because exon boundaries are also nucleosome enriched (Andersson et al 2009;Tilgner et al 2009), H2Bub1 density was normalized with respect to nucleosome occupancy (see Supplemental Methods). H2Bub1 was still enriched at the exon boundaries after this normalization (Fig.…”

Section: H2bub1 Is Highly Enriched At the Exon-intron Boundaries Of Hmentioning

confidence: 99%

H2B monoubiquitylation is a 5′-enriched active transcription mark and correlates with exon–intron structure in human cells

Jung

Kim²,

Kim³

et al. 2012

Genome Res.

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H2B monoubiquitylation (H2Bub1), which is required for multiple methylations of both H3K4 and H3K79, has been implicated in gene expression in numerous organisms ranging from yeast to human. However, the molecular crosstalk between H2Bub1 and other modifications, especially the methylations of H3K4 and H3K79, remains unclear in vertebrates. To better understand the functional role of H2Bub1, we measured genome-wide histone modification patterns in human cells. Our results suggest that H2Bub1 has dual roles, one that is H3 methylation dependent, and another that is H3 methylation independent. First, H2Bub1 is a 59-enriched active transcription mark and co-occupies with H3K79 methylations in actively transcribed regions. Second, this study shows for the first time that H2Bub1 plays a histone H3 methylationsindependent role in chromatin architecture. Furthermore, the results of this work indicate that H2Bub1 is largely positioned at the exon-intron boundaries of highly expressed exons, and it demonstrates increased occupancy in skipped exons compared with flanking exons in the human and mouse genomes. Our findings collectively suggest that a potentiating mechanism links H2Bub1 to both H3K79 methylations in actively transcribed regions and the exon-intron structure of highly expressed exons via the regulation of nucleosome dynamics during transcription elongation.

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Nucleosome positioning as a determinant of exon recognition

Cited by 405 publications

References 52 publications

Nucleosome fragility is associated with future transcriptional response to developmental cues and stress in C. elegans

Nucleosome fragility is associated with future transcriptional response to developmental cues and stress in C. elegans

Prediction of single‐nucleotide substitutions that result in exon skipping: identification of a splicing silencer inBRCA1exon 6

H2B monoubiquitylation is a 5′-enriched active transcription mark and correlates with exon–intron structure in human cells

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