Dynamic Lysine Methylation on Histone H3 Defines the Regulatory Phase of Gene Transcription

Morillon, Antonin; Karabetsou, Nickoletta; Nair, Anitha; Mellor, Jane

doi:10.1016/j.molcel.2005.05.009

Cited by 187 publications

(196 citation statements)

References 68 publications

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“…Interestingly, many stalled polymerases in normal cells are probably caused by structural obstacles to elongation, rather than by DNA damage. Stalling may be especially common for spuriously initiated polymerases that probably explain some of the transcriptional ''dark matter'' identified by recent tiling microarray experiments (55), or for ''pathfinder'' polymerases that begin the complex reorganization of chromatin structure downstream from a newly activated promoter (56).…”

Section: Discussionmentioning

confidence: 99%

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling

Newman

Bailey

Weiner³

2006

Proc. Natl. Acad. Sci. U.S.A.

137

129

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Cockayne syndrome (CS) is an inherited neurodevelopmental disorder with progeroid features. Although the genes responsible for CS have been implicated in a variety of DNA repair-and transcription-related pathways, the nature of the molecular defect in CS remains mysterious. Using expression microarrays and a unique method for comparative expression analysis called L2L, we sought to define this defect in cells lacking a functional CS group B (CSB) protein, the SWI͞SNF-like ATPase responsible for most cases of CS. Remarkably, many of the genes regulated by CSB are also affected by inhibitors of histone deacetylase and DNA methylation, as well as by defects in poly(ADP-ribose)-polymerase function and RNA polymerase II elongation. Moreover, consistent with these microarray expression data, CSB-null cells are sensitive to inhibitors of histone deacetylase or poly(ADP-ribose)-polymerase. Our data indicate a general role for CSB protein in maintenance and remodeling of chromatin structure and suggest that CS is a disease of transcriptional deregulation caused by misexpression of growthsuppressive, inflammatory, and proapoptotic pathways.DNA repair ͉ L2L ͉ microarray ͉ transcription C ockayne syndrome (CS) is a devastating inherited disease characterized by severe postnatal growth failure and progressive neurological dysfunction, along with a variety of symptoms reminiscent of aging, including retinal degeneration, sensorineural hearing loss, cataracts, and loss of subcutaneous fat (1). The nature of the molecular defect that causes CS remains elusive, although CS has been intensively studied for many years, and much is known about the cellular functions of the five genes responsible for the disease. Most cases of CS are caused by defects in two genes: CS groups A (CSA) and B (CSB). The CSB protein is a SWI͞SNF-like DNA-dependent ATPase (2-4) that can wind DNA (5) and remodel chromatin in vitro (6). CSB is required for translocation of the CSA protein to the nuclear matrix after DNA damage (7). Rare alleles of three xeroderma pigmentosum (XP) genes (XPB, XPD, and XPG) are responsible for the remaining cases of CS; these patients usually lack the severe predisposition to skin cancer typical of XP (8). CS genes have been implicated, alone or in various combinations, in transcription-coupled repair (TCR) of UV-induced DNA lesions (9, 10), repair of oxidative DNA damage (11), transcription initiation by RNA polymerase I (pol I; refs. 12 and 13) and RNA polymerase II (pol II; ref. 14), elongation by pol II (15, 16), transcription of induced genes (17), protein ubiquitination (18), and metaphase chromosome condensation (19).To understand how CSB defects cause CS, we characterized the array of genes regulated by CSB. Previous expression array studies, although encouraging, had not been conclusive (20) or had focused on the role of CS genes in the transcriptional response to oxidative (17) or ultraviolet (21) DNA damage. Our hope was to work backwards from effect to cause, deducing the biochemical functions of CSB from genes it...

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Section: Discussionmentioning

confidence: 99%

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling

Newman

Bailey

Weiner³

2006

Proc. Natl. Acad. Sci. U.S.A.

137

129

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“…This property suggests that the lysine-methyltransferase activity, including varying degrees of methylation (mono-, di-or tri-methylation), substrate specificity and localization can be subjected to regulation by intra-and inter-molecular interactions with other proteins. Indeed, modulation of the SET domain-mediated lysine-methyltransferase activity by interacting proteins has been demonstrated for yeast SET1-COMPASS [106,107] and for human MLL1 trithorax complex [108].…”

Section: Regulation Of Set Protein Functions Through Protein-protein mentioning

confidence: 99%

Plant SET domain-containing proteins: Structure, function and regulation

Wang

Chandrasekharan

et al. 2007

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

170

195

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Modification of the histone proteins that form the core around which chromosomal DNA is looped has profound epigenetic effects on the accessibility of the associated DNA for transcription, replication and repair. The SET domain is now recognized as generally having methyltransferase activity targeted to specific lysine residues of histone H3 or H4. There is considerable sequence conservation within the SET domain and within its flanking regions. Previous reviews have shown that SET proteins from Arabidopsis and maize fall into five classes according to their sequence and domain architectures. These classes generally reflect specificity for a particular substrate. SET proteins from rice were found to fall into similar groupings, strengthening the merit of the approach taken. Two additional classes, VI and VII, were established that include proteins with truncated/ interrupted SET domains. Diverse mechanisms are involved in shaping the function and regulation of SET proteins. These include protein-protein interactions through both intra-and inter-molecular associations that are important in plant developmental processes, such as flowering time control and embryogenesis. Alternative splicing that can result in the generation of two to several different transcript isoforms is now known to be widespread. An exciting and tantalizing question is whether, or how, this alternative splicing affects gene function. For example, it is conceivable that one isoform may debilitate methyltransferase function whereas the other may enhance it, providing an opportunity for differential regulation. The review concludes with the speculation that modulation of SET protein function is mediated by antisense or sense-antisense RNA.

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“…Recent data indicate that both the precise lysine residue modified and degree of methylation have differential effects on transcriptional regulation (17,18), suggesting that a combination of both parameters defines the epigenetic mark and its functional role.…”

mentioning

confidence: 99%

Cross-talk between Histone Modifications in Response to Histone Deacetylase Inhibitors

Nightingale

Gendreizig

White

et al. 2007

Journal of Biological Chemistry

185

160

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Histones are subject to a wide variety of post-translational modifications that play a central role in gene activation and silencing. We have used histone modification-specific antibodies to demonstrate that two histone modifications involved in gene activation, histone H3 acetylation and H3 lysine 4 methylation, are functionally linked. This interaction, in which the extent of histone H3 acetylation determines both the abundance and the "degree" of H3K4 methylation, plays a major role in the epigenetic response to histone deacetylase inhibitors. A combination of in vivo knockdown experiments and in vitro methyltransferase assays shows that the abundance of H3K4 methylation is regulated by the activities of two opposing enzyme activities, the methyltransferase MLL4, which is stimulated by acetylated substrates, and a novel and as yet unidentified H3K4me3 demethylase.A growing body of evidence suggests that many different types of post-translational histone modifications play key roles in regulating gene expression and that some modifications at least are functionally inter-related (1). The linked deposition of distinct modifications can occur both on the same histone tail, e.g. H3S10 phosphorylation and H3K9 acetylation (2) or on different tails, e.g. H2A ubiquitination and H3 methylation (3), histone acetylation, and methylation (4, 5). Multiprotein complexes have been identified that are capable of depositing, or removing, different modifications in a coordinated manner (e.g. histone demethylase and deacetylase activity in coREST) (6). Similarly, binding proteins are sensitive to combinations of modifications; for example, HP1 binding to the H3 tail requires histone H3K9 methylation but is blocked by H3S10 phosphorylation and H3K14 acetylation (Ref. 7, although see Ref. 8).This suggests that epigenetic marks are not deposited or recognized in isolation but comprise a complex and inter-related collection of modifications at adjacent residues.The correlation between different histone modifications is particularly clear for histone H3 acetylation and the methylation of histone H3 lysine 4 (H3K4me). Mass spectrometric analysis of the cellular pool of histones indicates that this methyl mark is associated with histone H3 molecules containing high levels of acetylation (9). This is consistent with the observed co-localization of these marks, which show related distribution patterns both at a chromosome-wide level during X inactivation (10) and over the coding regions of individual genes (11,12). These correlations may arise due to physical links between histone-modifying enzymes such that they are co-recruited to the same loci. Both MLL1, a histone methyltransferase (HMT) 2 that can generate H3K4me marks (13), and Chd1, the chromatin remodeler that is subsequently recruited by this methyl mark, associate with histone acetyltransferase activities (14, 15), whereas the LSD1 complex that removes some of these methyl marks contains the histone deacetylases HDAC1 and HDAC2 (16). However, the interaction could also arise ...

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Dynamic Lysine Methylation on Histone H3 Defines the Regulatory Phase of Gene Transcription

Cited by 187 publications

References 68 publications

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling

Plant SET domain-containing proteins: Structure, function and regulation

Cross-talk between Histone Modifications in Response to Histone Deacetylase Inhibitors

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