Histone Modification
Wrote by Mingyue Li PB11207062 2013/10/19
Of the various protein–DNA interactions that are central to genome function,those between the histones and DNA are among the most intimate. A histone–DNA complex, the nucleosome, is the basic unit of chromatin structure in nearly all eukaryotes, It comprises 146 bp of DNA wrapped in 1¾ superhelical turns around a core of eight histones, two each of H2A, H2B, H3, and H4.All core histones, apart from H4, have nonallelic variant forms that differ in amino acid sequence and are associated with specific cellular and genomic functions.
In the nearly 50 years since that seminal discovery, well over 100 distinct histone modifications have been described, with more being discovered at a rapid pace. All four core histones are subject to such changes, which include acetylation of lysines,methylation of lysines and arginines, phosphorylation of serines and threonines, and attachment of the small peptides ubiquitin and SUMO.Histone modifications are put in place and removed by families (often large) of modifying and de-modifying enzymes and are consistently dynamic. The level of any particular modification reflects a steady-state balance between the actions of these two sets of enzymes.
Here we examine the known properties of key histone modifications and the biological processes to which they are linked to place the modifications in the context of nucleosome dynamics —that is, processes in which nucleosomes are translocated, unwrapped, evicted or replaced. First ,DNA access through histone acetylation.Indeed, the chemistry of histone acetylation suggests a mechanism by which it might facilitate gene expression. Acetylation neutralizes the positive charge of lysine residues, weakening charge-dependent interactions between a histone and nucleosomal DNA, linker DNA or adjacent histones, and thus increasing the accessibility of DNA to the transcription machinery. It has recently been shown that histone
acetylation is associated with productive origin activation, suggesting that charge neutralization of lysines is important not only for proper transcription but also for efficient DNA replication by relaxing histone-DNA contacts. Histone acetylation also occurs at DNA double-strand breaks and may therefore be used to increase DNA access for repair factors.Second ,Histone methylations as regulatory modules. It has been suggested that H3K4me3 and H3K36me3 may function as regulatory modules in some contexts. In vitro, H3K4me3 inhibits trimethylation of H3K27 by the
D. melanogaster and human variants of Polycomb repressive complex 2. In vivo , the Trithorax complex antagonizes Polycomb silencing through the establishment of H3K4me3, and Trithorax-mediated H3K4me3 may thus have an anti-repressor function through inhibition of H3K27me3 methylation.In the case of H3K9me3 and H3K27me3, which are associated with heterochromatin formation and Polycomb silencing, respectively, methylation increases the affinity of certain protein modules for histone residues. H3K36me3 also has a role in stabilizing nucleosomes. It was initially observed that H3K36me3, established cotranscriptionally by Set2, was involved in suppressing cryptic transcription in gene bodies. Third, DNA access through histone phosphorylation.Phosphorylation is the chemical means by which the majority of signals are transduced in a cell. Phosphorylation imparts a negative charge to its modified residue, and this fact suggests that histone phosphorylation has a similar role to acetylation in modulating nucleosome dynamics.Histone phosphorylation also alters the affinity of chromatin-binding proteins for their targets. Phosphorylation of residues adjacent to a meth-ylated lysine reduces the affinity of the lysine residue’s cognate methyl-binding protein.Additionally ,ADP ribosylation and Glycosylation also important.ADP ribosylation imparts a negative charge to its modified residues, suggesting that this modification creates charge repulsion between histones and DNA, similar to
phosphorylation,while,total histone O-GlcNAcylation increases with heat shock and is cor-related with decreased sensitivity of chromatin to microccocal nuclease digestion, suggesting that this modification might be involved in transcriptional repression66. However, it is unclear how histone O-GlcNAcylation might lead to decreased chromatin accessibility.
Well over 100 histone modifications have been described, and it is likely that other forms and sites of modification will be uncovered. The large number of known and potential histone modifications has led to the suggestion that there would be a high degree of combinato-rial complexity in modification patterns in vivo .Studies point to a view of histone modifications as cogs in dynamic chromatin processes, wherein histone modifications reinforce changes in nucleosome occupancy, positioning or composition mediated by processes such as transcriptional elongation, chromatin remodeling and the targeting actions of noncoding RNAs.
References:
[1]Gabriel E Zentner & Steven Henikoff. Regulation of nucleosome dynamics by histone modifications. Nature structural & molecular biology.2013 Mar;20(3):259-66.
[2]Campbell MJ&Turner BM. Altered histone modification in cancer. Adv Exp Med Biol .2013;754:81-107.
Histone Modification
Wrote by Mingyue Li PB11207062 2013/10/19
Of the various protein–DNA interactions that are central to genome function,those between the histones and DNA are among the most intimate. A histone–DNA complex, the nucleosome, is the basic unit of chromatin structure in nearly all eukaryotes, It comprises 146 bp of DNA wrapped in 1¾ superhelical turns around a core of eight histones, two each of H2A, H2B, H3, and H4.All core histones, apart from H4, have nonallelic variant forms that differ in amino acid sequence and are associated with specific cellular and genomic functions.
In the nearly 50 years since that seminal discovery, well over 100 distinct histone modifications have been described, with more being discovered at a rapid pace. All four core histones are subject to such changes, which include acetylation of lysines,methylation of lysines and arginines, phosphorylation of serines and threonines, and attachment of the small peptides ubiquitin and SUMO.Histone modifications are put in place and removed by families (often large) of modifying and de-modifying enzymes and are consistently dynamic. The level of any particular modification reflects a steady-state balance between the actions of these two sets of enzymes.
Here we examine the known properties of key histone modifications and the biological processes to which they are linked to place the modifications in the context of nucleosome dynamics —that is, processes in which nucleosomes are translocated, unwrapped, evicted or replaced. First ,DNA access through histone acetylation.Indeed, the chemistry of histone acetylation suggests a mechanism by which it might facilitate gene expression. Acetylation neutralizes the positive charge of lysine residues, weakening charge-dependent interactions between a histone and nucleosomal DNA, linker DNA or adjacent histones, and thus increasing the accessibility of DNA to the transcription machinery. It has recently been shown that histone
acetylation is associated with productive origin activation, suggesting that charge neutralization of lysines is important not only for proper transcription but also for efficient DNA replication by relaxing histone-DNA contacts. Histone acetylation also occurs at DNA double-strand breaks and may therefore be used to increase DNA access for repair factors.Second ,Histone methylations as regulatory modules. It has been suggested that H3K4me3 and H3K36me3 may function as regulatory modules in some contexts. In vitro, H3K4me3 inhibits trimethylation of H3K27 by the
D. melanogaster and human variants of Polycomb repressive complex 2. In vivo , the Trithorax complex antagonizes Polycomb silencing through the establishment of H3K4me3, and Trithorax-mediated H3K4me3 may thus have an anti-repressor function through inhibition of H3K27me3 methylation.In the case of H3K9me3 and H3K27me3, which are associated with heterochromatin formation and Polycomb silencing, respectively, methylation increases the affinity of certain protein modules for histone residues. H3K36me3 also has a role in stabilizing nucleosomes. It was initially observed that H3K36me3, established cotranscriptionally by Set2, was involved in suppressing cryptic transcription in gene bodies. Third, DNA access through histone phosphorylation.Phosphorylation is the chemical means by which the majority of signals are transduced in a cell. Phosphorylation imparts a negative charge to its modified residue, and this fact suggests that histone phosphorylation has a similar role to acetylation in modulating nucleosome dynamics.Histone phosphorylation also alters the affinity of chromatin-binding proteins for their targets. Phosphorylation of residues adjacent to a meth-ylated lysine reduces the affinity of the lysine residue’s cognate methyl-binding protein.Additionally ,ADP ribosylation and Glycosylation also important.ADP ribosylation imparts a negative charge to its modified residues, suggesting that this modification creates charge repulsion between histones and DNA, similar to
phosphorylation,while,total histone O-GlcNAcylation increases with heat shock and is cor-related with decreased sensitivity of chromatin to microccocal nuclease digestion, suggesting that this modification might be involved in transcriptional repression66. However, it is unclear how histone O-GlcNAcylation might lead to decreased chromatin accessibility.
Well over 100 histone modifications have been described, and it is likely that other forms and sites of modification will be uncovered. The large number of known and potential histone modifications has led to the suggestion that there would be a high degree of combinato-rial complexity in modification patterns in vivo .Studies point to a view of histone modifications as cogs in dynamic chromatin processes, wherein histone modifications reinforce changes in nucleosome occupancy, positioning or composition mediated by processes such as transcriptional elongation, chromatin remodeling and the targeting actions of noncoding RNAs.
References:
[1]Gabriel E Zentner & Steven Henikoff. Regulation of nucleosome dynamics by histone modifications. Nature structural & molecular biology.2013 Mar;20(3):259-66.
[2]Campbell MJ&Turner BM. Altered histone modification in cancer. Adv Exp Med Biol .2013;754:81-107.