Two strategies for gene regulation by promoter nucleosomes

Tirosh, Itay; Barkai, Naama

doi:10.1101/gr.076059.108

Cited by 368 publications

(539 citation statements)

References 47 publications

(87 reference statements)

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“…Our results are reminiscent of previous reports from yeast, which propose that promoter structures can generally be classified as containing depleted proximal nucleosomes (DPNs) or occupied proximal nucleosomes (OPNs) (Tirosh and Barkai 2008). In yeast, DPN genes have low transcriptional plasticity (defined as the capacity to modulate transcription levels upon changing conditions), have well positioned nucleosomes, and are enriched for TF binding sites and H2A.Z.…”

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

confidence: 84%

Nucleosome fragility is associated with future transcriptional response to developmental cues and stress inC. 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: 84%

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

Jeffers

Lieb

2016

Genome Res.

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“…The TATA box was also implicated in high responsiveness to environmental perturbations (Basehoar et al 2004;Kim 2008, 2009;Tirosh and Barkai 2008;Lehner 2010). To examine whether eliminating the TATA box modulates the responsiveness to environmental changes, we measured the fold change in expression of different TATA mutant promoters following different environmental perturbations (Methods).…”

Section: Unique Effect Of Tata Box Mutations On the Response To Envirmentioning

confidence: 99%

“…The expression of genes deviating from the scaling curve, displaying higherthan-expected noise (Bar-Even et al 2006;Newman et al 2006), was more responsive to changing conditions and also diverged more between related species (Tirosh and Barkai 2008;Choi and Kim 2009;Lehner 2010). Notably, high noise, responsiveness, and divergence were all correlated with the organization of gene promoters: All three measures were low in promoters lacking a TATA box and containing a nucleosome free region (NFR) proximal to the transcription start site (referred to as DPN promoters-depleted proximal nucleosome), and were high in TATA-containing promoters that lack NFR (OPN, occupied proximal nucleosome) (Field et al 2008;Tirosh and Barkai 2008;Choi and Kim 2009). TATA box was also shown to increase noise in Pho5 expression (Raser and O'Shea 2004) and in synthetic promoters (Blake et al 2006;Murphy et al 2010).…”

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confidence: 99%

Noise–mean relationship in mutated promoters

Hornung¹,

Bar‐Ziv²,

Rosin³

et al. 2012

Genome Res.

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Gene expression depends on the frequency of transcription events (burst frequency) and on the number of mRNA molecules made per event (burst size). Both processes are encoded in promoter sequence, yet their dependence on mutations is poorly understood. Theory suggests that burst size and frequency can be distinguished by monitoring the stochastic variation (noise) in gene expression: Increasing burst size will increase mean expression without changing noise, while increasing burst frequency will increase mean expression and decrease noise. To reveal principles by which promoter sequence regulates burst size and frequency, we randomly mutated 22 yeast promoters chosen to span a range of expression and noise levels, generating libraries of hundreds of sequence variants. In each library, mean expression (m) and noise (coefficient of variation, h) varied together, defining a scaling curve: h 2 = b/m + h ext 2 . This relation is expected if sequence mutations modulate burst frequency primarily. The estimated burst size (b) differed between promoters, being higher in promoter containing a TATA box and lacking a nucleosome-free region. The rare variants that significantly decreased b were explained by mutations in TATA, or by an insertion of an out-of-frame translation start site. The decrease in burst size due to mutations in TATA was promoter-dependent, but independent of other mutations. These TATA box mutations also modulated the responsiveness of gene expression to changing conditions. Our results suggest that burst size is a promoter-specific property that is relatively robust to sequence mutations but is strongly dependent on the interaction between the TATA box and promoter nucleosomes.

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“…However, in contrast to the effect of TATA-boxes and TF sites, chromatin was suggested to mainly affect the frequency with which promoters transition between transcriptionally active and inactive states (Raser and O'Shea 2004). In yeast, statistically significant genome-wide associations were found between higherexpression variability and the presence of TATA-boxes, the number of TF binding sites, and the encoding of high nucleosome occupancy (Field et al 2008;Tirosh et al 2008).…”

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confidence: 99%

Two DNA-encoded strategies for increasing expression with opposing effects on promoter dynamics and transcriptional noise

et al. 2013

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Individual cells from a genetically identical population exhibit substantial variation in gene expression. A significant part of this variation is due to noise in the process of transcription that is intrinsic to each gene, and is determined by factors such as the rate with which the promoter transitions between transcriptionally active and inactive states, and the number of transcripts produced during the active state. However, we have a limited understanding of how the DNA sequence affects such promoter dynamics. Here, we used single-cell time-lapse microscopy to compare the effect on transcriptional dynamics of two distinct types of sequence changes in the promoter that can each increase the mean expression of a cell population by similar amounts but through different mechanisms. We show that increasing expression by strengthening a transcription factor binding site results in slower promoter dynamics and higher noise as compared with increasing expression by adding nucleosome-disfavoring sequences. Our results suggest that when achieving the same mean expression, the strategy of using stronger binding sites results in a larger number of transcripts produced from the active state, whereas the strategy of adding nucleosome-disfavoring sequences results in a higher frequency of promoter transitions between active and inactive states. In the latter strategy, this increased sampling of the active state likely reduces the expression variability of the cell population. Our study thus demonstrates the effect of cis-regulatory elements on expression variability and points to concrete types of sequence changes that may allow partial decoupling of expression level and noise.

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Two strategies for gene regulation by promoter nucleosomes

Cited by 368 publications

References 47 publications

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

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

Noise–mean relationship in mutated promoters

Two DNA-encoded strategies for increasing expression with opposing effects on promoter dynamics and transcriptional noise

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