Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation (original) (raw)
Related papers
Molecular Cell, 2010
Lysine 9 of histone 3 (H3K9) can be mono-, di-, or trimethylated, inducing distinct effects on gene expression and chromatin compaction. H3K9 methylation can be mediated by several histone methyltransferases (HKMTs) that possess mono-, di-, or trimethylation activities. Here we provide evidence that a subset of each of the main H3K9 HKMTs, G9a/KMT1C, GLP/KMT1D, SETDB1/KMT1E, and Suv39h1/KMT1A, coexist in the same megacomplex. Moreover, in Suv39h or G9a null cells, the remaining HKMTs are destabilized at the protein level, indicating that the integrity of these HKMTs is interdependent. The four HKMTs are recruited to major satellite repeats, a known Suv39h1 genomic target, but also to multiple G9a target genes. Moreover, we report a functional cooperation between the four H3K9 HKMTs in the regulation of known G9a target genes. Altogether, our data identify a H3K9 methylation multimeric complex.
Methylation of histone H3 Lys 4 in coding regions of active genes
Proceedings of The National Academy of Sciences, 2002
Posttranslational modifications of histone tails regulate chromatin structure and transcription. Here we present global analyses of histone acetylation and histone H3 Lys 4 methylation patterns in yeast. We observe a significant correlation between acetylation of histones H3 and H4 in promoter regions and transcriptional activity. In contrast, we find that dimethylation of histone H3 Lys 4 in coding regions correlates with transcriptional activity. The histone methyltransferase Set1 is required to maintain expression of these active, promoter-acetylated, and coding region-methylated genes. Global comparisons reveal that genomic regions deacetylated by the yeast enzymes Rpd3 and Hda1 overlap extensively with Lys 4 hypo-but not hypermethylated regions. In the context of recent studies showing that Lys 4 methylation precludes histone deacetylase recruitment, we conclude that Set1 facilitates transcription, in part, by protecting active coding regions from deacetylation.
Regulation of chromatin structure by site-specific histone H3 methyltransferases
Nature, 2000
The organization of chromatin into higher-order structures in¯uences chromosome function and epigenetic gene regulation. Higher-order chromatin has been proposed to be nucleated by the covalent modi®cation of histone tails and the subsequent establishment of chromosomal subdomains by non-histone modi®er factors. Here we show that human SUV39H1 and murine Suv39h1Ðmammalian homologues of Drosophila Su(var)3-9 and of Schizosaccharomyces pombe clr4Ðencode histone H3-speci®c methyltransferases that selectively methylate lysine 9 of the amino terminus of histone H3 in vitro. We mapped the catalytic motif to the evolutionarily conserved SET domain, which requires adjacent cysteine-rich regions to confer histone methyltransferase activity. Methylation of lysine 9 interferes with phosphorylation of serine 10, but is also in¯uenced by preexisting modi®cations in the amino terminus of H3. In vivo, deregulated SUV39H1 or disrupted Suv39h activity modulate H3 serine 10 phosphorylation in native chromatin and induce aberrant mitotic divisions. Our data reveal a functional interdependence of site-speci®c H3 tail modi®cations and suggest a dynamic mechanism for the regulation of higher-order chromatin.
Journal of Biological Chemistry, 2002
Histone N-terminal tails are post-translationally modified in many ways. At lysine residues, histones can be either acetylated or methylated. Both modifications lead to the binding of specific proteins; bromodomain proteins, such as GCN5, bind acetyl lysines and the chromodomain protein, HP1, binds methyl lysine 9 of histone H3. Here we show that the previously characterized transcriptional repressor complex NuRD (nucleosome remodeling and deacetylase) binds to the histone H3 N-terminal tail and that methylation at lysine 4, but not lysine 9, prevents binding. Given that lysine 4 methylation is found at sites of active transcription, these results suggest that a function of lysine 4 methylation is to disrupt the association of histones with a repressor complex.
Histone H3 Lysine 4 Mono-methylation does not Require Ubiquitination of Histone H2B
Journal of Molecular Biology, 2005
The yeast Set1-complex catalyzes histone H3 lysine 4 (H3K4) methylation. Using N-terminal Edman sequencing, we determined that 50% of H3K4 is methylated and consists of roughly equal amounts of mono, di and trimethylated H3K4. We further show that loss of either Paf1 of the Paf1 elongation complex, or ubiquitination of histone H2B, has only a modest effect on bulk histone mono-methylation at H3K4. Despite the fact that Set1 recruitment decreases in paf1D cells, loss of Paf1 results in an increase of H3K4 mono-methylation at the 5 0 coding region of active genes, suggesting a Paf1-independent targeting of Set1. In contrast to Paf1 inactivation, deleting RTF1 affects H3K4 mono-methylation at the 3 0 coding region of active genes and results in a decrease of global H3K4 mono-methylation.
The Journal of biological chemistry, 2006
Set1 is the catalytic subunit and the central component of the evolutionarily conserved Set1 complex (Set1C) that methylates histone 3 lysine 4 (H3K4). Here we have determined protein/protein interactions within the complex and related the substructure to function. The loss of individual Set1C subunits differentially affects Set1 stability, complex integrity, global H3K4 methylation, and distribution of H3K4 methylation along active genes. The complex requires Set1, Swd1, and Swd3 for integrity, and Set1 amount is greatly reduced in the absence of the Swd1-Swd3 heterodimer. Bre2 and Sdc1 also form a heteromeric subunit, which requires the SET domain for interaction with the complex, and Sdc1 strongly interacts with itself. Inactivation of either Bre2 or Sdc1 has very similar effects. Neither is required for complex integrity, and their removal results in an increase of H3K4 mono- and dimethylation and a severe decrease of trimethylation at the 5' end of active coding regions but...
PloS one, 2016
Posttranslational modifications (PTMs) of proteins play a crucial role in regulating protein-protein interactions, enzyme activity, subcellular localization, and stability of the protein. SET domain, bifurcated 1 (SETDB1) is a histone methyltransferase that regulates the methylation of histone H3 on lysine 9 (H3K9), gene silencing, and transcriptional repression. The C-terminal region of SETDB1 is a key site for PTMs, and is essential for its enzyme activity in mammalian and insect cells. In this study, we aimed to evaluate more precisely the effect of PTMs on the H3K9 methyltransferase activity of SETDB1. Using mass spectrometry analysis, we show that the C-terminal region of human SETDB1 purified from insect cells is ubiquitinated. We also demonstrate that the ubiquitination of lysine 867 of the human SETDB1 is necessary for full H3K9 methyltransferase activity in mammalian cells. Finally, we show that SETDB1 ubiquitination regulates the expression of its target gene, serpin pepti...
Purification and Functional Characterization of a Histone H3Lysine 4Specific Methyltransferase
Molecular Cell, 2001
including lysines 4, 9, 27, and 36 of H3 and lysine 20 of H4, are preferred sites of methylation (reviewed in ). Based on the observaongoing methylation (Annunziato et al., 1995; Hendzel Lineberger Comprehensive Cancer Center and Davie, 1989; Strahl et al., 1999), it has been sug-University of North Carolina at Chapel Hill gested that histone methylation may have a role in tran-Chapel Hill, North Carolina 27599 scriptional regulation. However, direct evidence linking 2 Molecular Biology Program histone methylation to gene activity was not available Memorial Sloan Kettering Cancer Center until recently. One major obstacle in studying the func-New York, New York 10021 tion of histone methylation is the lack of information regarding the responsible enzymes. Great progress has been made in the identification Summary and characterization of HMTases recently (Jenuwein and Allis, 2001; Zhang and Reinberg, 2001). Importantly, Methylation of histone H3 at lysine 9 by SUV39H1 and methylation of histones at different residues seems to subsequent recruitment of the heterochromatin proplay distinctive roles in transcriptional regulation (Jenutein HP1 has recently been linked to gene silencing. wein and Allis, 2001; Zhang and Reinberg, 2001).
Cell, 2005
Yeast Rpd3 histone deacetylase plays an important role at actively transcribed genes. We characterized two distinct Rpd3 complexes, Rpd3L and Rpd3S, by MudPIT analysis. Both complexes shared a three subunit core and Rpd3L contains unique subunits consistent with being a promoter targeted corepressor. Rco1 and Eaf3 were subunits specific to Rpd3S. Mutants of RCO1 and EAF3 exhibited increased acetylation in the FLO8 and STE11 open reading frames (ORFs) and the appearance of aberrant transcripts initiating within the body of these ORFs. Mutants in the RNA polymerase II-associated SET2 histone methyltransferase also displayed these defects. Set2 functioned upstream of Rpd3S and the Eaf3 methylhistone binding chromodomain was important for recruitment of Rpd3S and for deacetylation within the STE11 ORF. These data indicate that Pol II-associated Set2 methylates H3 providing a transcriptional memory which signals for deacetylation of ORFs by Rpd3S. This erases transcription elongation-associated acetylation to suppress intragenic transcription initiation.
Set2 methylation of histone H3 lysine 36 suppresses histone exchange on transcribed genes
Set2-mediated methylation of histone H3 at Lys 36 (H3K36me) is a co-transcriptional event that is necessary for the activation of the Rpd3S histone deacetylase complex, thereby maintaining the coding region of genes in a hypoacetylated state 1,2 . In the absence of Set2, H3K36 or Rpd3S acetylated histones accumulate on open reading frames (ORFs), leading to transcription initiation from cryptic promoters within ORFs 1,3 . Although the co-transcriptional deacetylation pathway is well characterized, the factors responsible for acetylation are as yet unknown. Here we show that, in yeast, co-transcriptional acetylation is achieved in part by histone exchange over ORFs. In addition to its function of targeting and activating the Rpd3S complex, H3K36 methylation suppresses the interaction of H3 with histone chaperones, histone exchange over coding regions and the incorporation of new acetylated histones. Thus, Set2 functions both to suppress the incorporation of acetylated histones and to signal for the deacetylation of these histones in transcribed genes. By suppressing spurious cryptic transcripts from initiating within ORFs, this pathway is essential to maintain the accuracy of transcription by RNA polymerase II.