Histone modifications: Combinatorial complexity or cumulative simplicity?

Henikoff, Steven

doi:10.1073/pnas.0501853102

Cited by 87 publications

(61 citation statements)

References 29 publications

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“…First, microarray analyses have shown that irrespective of K5, K8 or K12 being substituted with Arg to mimic the non-acetylated, positively charged state of lysine, the resultant changes in gene expression patterns were similar, suggesting that these three lysines were interchangeable and that their acetylation likely negated general charge effects. This was in contrast to the case of K16 in which substitution with Arg gave rise to a markedly distinctive pattern of altered gene expression (Dion et al, 2005, Henikoff, 2005.…”

Section: Histone H4 Lysine 16 Acetylationcontrasting

confidence: 75%

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

2007

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Histone deacetylases (HDACs) catalyse the removal of acetyl groups from the N-terminal tails of histones. All known HDACs can be categorized into one of four classes (I-IV). The class III HDAC or silencing information regulator 2 (Sir2) family exhibits characteristics consistent with a distinctive role in regulation of chromatin structure. Accumulating data suggest that these deacetylases acquired new roles as genomic complexity increased, including deacetylation of non-histone proteins and functional diversification in mammals. However, the intrinsic regulation of chromatin structure in species as diverse as yeast and humans, underscores the pressure to conserve core functions of class III HDACs, which are also known as Sirtuins. One of the key factors that might have contributed to this preservation is the intimate relationship between some members of this group of proteins (SirT1, SirT2 and SirT3) and deacetylation of a specific residue in histone H4, lysine 16 (H4K16). Evidence accumulated over the years has uncovered a unique role for H4K16 in chromatin structure throughout eukaryotes. Here, we review the recent findings about the functional relationship between H4K16 and the Sir2 class of deacetylases and how that relationship might impact aging and diseases including cancer and diabetes.

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Section: Histone H4 Lysine 16 Acetylationcontrasting

confidence: 75%

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

2007

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“…Given this, it is possible that the influence of nucleosome occupancy on regulatory factor binding patterns represents the endpoint of many epigenetic mechanisms that control utilization of genetic information. This hypothesis would be consistent with the idea of a simplified and cumulative epigenetic code (Henikoff 2005) and with the idea that the DNA sequence of eukaryotic genomes has the capacity to directly encode nucleosome position and occupancy (Sekinger et al 2005;Yuan et al 2005;Segal et al 2006). The generation of distinct genomic binding patterns with identical genomic DNA, as we demonstrate here, may represent the essence of epigenetic phenomena observed in living eukaryotic cells.…”

Section: Control Of Nucleosome Occupancy As the Endpoint Of Epigenetisupporting

confidence: 70%

Whole-genome comparison of Leu3 binding in vitro and in vivo reveals the importance of nucleosome occupancy in target site selection

Liu¹,

Lee²,

Granek³

et al. 2006

Genome Res.

128

121

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Sequence motifs that are potentially recognized by DNA-binding proteins occur far more often in genomic DNA than do observed in vivo protein–DNA interactions. To determine how chromatin influences the utilization of particular DNA-binding sites, we compared the in vivo genome-wide binding location of the yeast transcription factor Leu3 to the binding location observed on the same genomic DNA in the absence of any protein cofactors. We found that the DNA-sequence motif recognized by Leu3 in vitro and in vivo was functionally indistinguishable, but Leu3 bound different genomic locations under the two conditions. Accounting for nucleosome occupancy in addition to DNA-sequence motifs significantly improved the prediction of protein–DNA interactions in vivo, but not the prediction of sites bound by purified Leu3 in vitro. Use of histone modification data does not further improve binding predictions, presumably because their effect is already manifest in the global histone distribution. Measurements of nucleosome occupancy in strains that differ in Leu3 genotype show that low nucleosome occupancy at loci bound by Leu3 is not a consequence of Leu3 binding. These results permit quantitation of the epigenetic influence that chromatin exerts on DNA binding-site selection, and provide evidence for an instructive, functionally important role for nucleosome occupancy in determining patterns of regulatory factor targeting genome-wide.

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“…Drugs inhibiting DNA methyltransferases, such as Vizada (5-azacytidine) and the related Decitabine, are now established agents in the treatment of cancer, as they have the potential to re-activate specific tumour suppressor genes. Probably even closer to the steering centre are the elaborate principles of the "histone code", which determines how covalent histone modifications such as acetylation, methylation and PAR-addition modify chromatin accessibility to enable or tune gene expression (Hake 2004;Henikoff 2005). This code has become indispensable for cancer specialists who utilize its principles to develop diagnostic tools and drugs.…”

Section: Outlook and Perspectivesmentioning

confidence: 99%