Regulated nucleosome mobility and the histone code

Cosgrove, Michael S.; Boeke, Jef D.; Wolberger, Cynthia

doi:10.1038/nsmb851

Cited by 360 publications

(310 citation statements)

References 73 publications

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“…nucleosome positioning may be one mechanism by which RelB promotes transcription silencing and tolerance. Although it is well established that the overall stability of nucleosome depends on its constituent DNA sequence and histone modifications (18,50), how such stability takes place is not clearly understood (51). Our striking finding that H3K9me2 modification always associated with stable nucleosomes, either in a basal/silent position (R0) or in a repressive position (T0 and T1), whereas H3K4me3 associated with permissive/open positions, suggests that histone methylation may play a role in nucleosome positioning.…”

Section: Discussionmentioning

confidence: 85%

Dynamic and Selective Nucleosome Repositioning during Endotoxin Tolerance

Gazzar

Liu

Yoza

et al. 2010

Journal of Biological Chemistry

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Sepsis is encoded by a sequel of transcription activation and repression events that initiate, sustain, and resolve severe systemic inflammation. The repression/silencing phase occurs in blood leukocytes of animals and humans following the initiation of systemic inflammation due to developing endotoxin tolerance. We previously reported that NF-B transcription factor RelB and histone H3 lysine methyltransferase G9a directly interact to induce facultative heterochromatin assembly and regulate epigenetic silencing during endotoxin tolerance, which is a major feature of sepsis. The general objective of this study was to assess whether dynamic temporal, structural, and positional changes of nucleosomes influence the sepsis phenotype. We used the THP-1 sepsis cell model to isolate mononucleosomes by rapid cell permeabilization and digestion of chromatin with micrococcal nuclease and then compared tumor necrosis factor ␣ (TNF␣) proximal promoter nucleosome alignment in endotoxin-responsive and -tolerant phenotypes. We found differential and dynamic repositioning of nucleosomes from permissive to repressive locations during the activation and silencing phases of transcription reprogramming and identified the following mechanisms that may participate in the process. 1) Two proximal nucleosomes repositioned to expose the primary NF-B DNA binding site in endotoxin-responsive cells, and this "promoter opening" required the ATP-independent chaperone NAP1 to replace the core histone H2A with the H2A.Z variant. 2) During RelB-dependent endotoxin tolerance, the two nucleosomes repositioned and masked the primary NF-B DNA binding site. 3) Small interfering RNA-mediated inhibition of RelB expression prevented repressive nucleosome repositioning and tolerance induction, but the "open" promoter required endotoxin-induced NF-B p65 promoter binding to initiate transcription, supporting the known requirement of p65 posttranslational modifications for transactivation. 4) Sustaining the permissive promoter state after RelB knockdown required ATP-dependent nucleosome remodeler BAF complex. Moreover, we found that forced expression of RelB in responsive cells induced repressive nucleosome positioning and silenced TNF␣ transcription, demonstrating the plasticity of nucleosome remodeling and its dependence on RelB. Our data suggest that nucleosome repositioning controls both the induction and epigenetic silencing phases of TNF␣ transcription associated with sepsis.

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Section: Discussionmentioning

confidence: 85%

Dynamic and Selective Nucleosome Repositioning during Endotoxin Tolerance

Gazzar

Liu

Yoza

et al. 2010

Journal of Biological Chemistry

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“…While most of the PTMs with known in vivo roles are located in the N-terminal tails, mounting evidence suggests that PTMs of core histones are as important (73,74), particularly to regulation of DNA accessibility (75). A large number of core histone PTMs are known to exist (76), investigation of their functional roles is an active area of research (74).…”

Section: Enhanced Accessibility To Ptm Sitesmentioning

confidence: 99%

Partially Assembled Nucleosome Structures at Atomic Detail

Rychkov

Ilatovskiy

Nazarov

et al. 2017

Biophysical Journal

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The evidence is now overwhelming that partially assembled nucleosome states (PANS) are as important as the canonical nucleosome structure for the understanding of how accessibility to genomic DNA is regulated in cells. We use a combination of molecular dynamics simulation and atomic force microscopy to deliver, in atomic detail, structural models of three key PANS: the hexasome (H2A$H2B)$(H3$H4) 2 , the tetrasome (H3$H4) 2 , and the disome (H3$H4). Despite fluctuations of the conformation of the free DNA in these structures, regions of protected DNA in close contact with the histone core remain stable, thus establishing the basis for the understanding of the role of PANS in DNA accessibility regulation. On average, the length of protected DNA in each structure is roughly 18 basepairs per histone protein. Atomistically detailed PANS are used to explain experimental observations; specifically, we discuss interpretation of atomic force microscopy, Fö rster resonance energy transfer, and small-angle x-ray scattering data obtained under conditions when PANS are expected to exist. Further, we suggest an alternative interpretation of a recent genome-wide study of DNA protection in active chromatin of fruit fly, leading to a conclusion that the three PANS are present in actively transcribing regions in a substantial amount. The presence of PANS may not only be a consequence, but also a prerequisite for fast transcription in vivo.

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“…9,10 However, K120 is also acetylated in bulk histones preparations. 11 It is intuitive to assume that these PTMs are mutually exclusive; however, genome-wide analysis suggested that H2BK120ac is part of a "signature" of 17 histone PTMs that mark core promoters of active genes. 12 The well established notion that core promoters are nucleosome-free is at odds with the finding of most of these PTMs in histones positioned in such areas, a fact that could be rationalized by the relative imprecision of sonicated chromatinbased assays.…”

Section: Introductionmentioning

confidence: 99%