Histone H3 Methylation by Set2 Directs Deacetylation of Coding Regions by Rpd3S to Suppress Spurious Intragenic Transcription (original) (raw)
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Cotranscriptional Set2 Methylation of Histone H3 Lysine 36 Recruits a Repressive Rpd3 Complex
Cell, 2005
The yeast histone deacetylase Rpd3 can be recruited to promoters to repress transcription initiation. Biochemical, genetic, and gene-expression analyses show that Rpd3 exists in two distinct complexes. The smaller complex, Rpd3C(S), shares Sin3 and Ume1 with Rpd3C(L) but contains the unique subunits Rco1 and Eaf3. Rpd3C(S) mutants exhibit phenotypes remarkably similar to those of Set2, a histone methyltransferase associated with elongating RNA polymerase II. Chromatin immunoprecipitation and biochemi-cal experiments indicate that the chromodomain of Eaf3 recruits Rpd3C(S) to nucleosomes methylated by Set2 on histone H3 lysine 36, leading to deacetylation of transcribed regions. This pathway apparently acts to negatively regulate transcription because deleting the genes for Set2 or Rpd3C(S) bypasses the requirement for the positive elongation factor Bur1/ Bur2.
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.
Proceedings of the National Academy of Sciences, 2002
Histone methylation has emerged as an important mechanism for regulating the transcriptional accessibility of chromatin. Several methyltransferases have been shown to target histone aminoterminal tails and mark nucleosomes associated with either euchromatic or heterochromatic states. However, the biochemical machinery responsible for regulating histone methylation and integrating it with other cellular events has not been well characterized. We report here the purification, molecular identification, and genetic and biochemical characterization of the Set1 protein complex that is necessary for methylation of histone H3 at lysine residue 4 in Saccharomyces cerevisiae. The seven-member 363-kDa complex contains homologs of Drosophila melanogaster proteins Ash2 and Trithorax and Caenorhabditis elegans protein DPY-30, which are implicated in the maintenance of Hox gene expression and regulation of X chromosome dosage compensation, respectively. Mutations of Set1 protein comparable to those that disrupt developmental function of its Drosophila homolog Trithorax abrogate histone methylation in yeast. These studies suggest that epigenetic regulation of developmental and sex-specific gene expression are species-specific readouts for a common chromatin remodeling machinery associated mechanistically with histone methylation.
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.
Specificity of the HP1 chromo domain for the methylated N-terminus of histone H3
The EMBO Journal, 2001
Recent studies show that heterochromatin-associated protein-1 (HP1) recognizes a`histone code' involving methylated Lys9 (methyl-K9) in histone H3. Using in situ immuno¯uorescence, we demonstrate that methyl-K9 H3 and HP1 co-localize to the heterochromatic regions of Drosophila polytene chromosomes. NMR spectra show that methyl-K9 binding of HP1 occurs via its chromo (chromosome organization modi®er) domain. This interaction requires methyl-K9 to reside within the proper context of H3 sequence. NMR studies indicate that the methylated H3 tail binds in a groove of HP1 consisting of conserved residues. Using¯uorescence anisotropy and isothermal titration calorimetry, we determined that this interaction occurs with a K D of~100 mM, with the binding enthalpically driven. A V26M mutation in HP1, which disrupts its gene silencing function, severely destabilizes the H3-binding interface, and abolishes methyl-K9 H3 tail binding. Finally, we note that sequence diversity in chromo domains may lead to diverse functions in eukaryotic gene regulation. For example, the chromo domain of the yeast histone acetyltransferase Esa1 does not interact with methyl-K9 H3, but instead shows preference for unmodi®ed H3 tail.
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.
Genes & Development, 2002
A novel histone methyltransferase, termed Set9, was isolated from human cells. Set9 contains a SET domain, but lacks the pre-and post-SET domains. Set9 methylates specifically lysine 4 (K4) of histone H3 (H3-K4) and potentiates transcription activation. The histone H3 tail interacts specifically with the histone deacetylase NuRD complex. Methylation of histone H3-K4 by Set9 precludes the association of NuRD with the H3 tail. Moreover, methylation of H3-K4 impairs Suv39h1-mediated methylation at K9 of H3 (H3-K9). The interplay between the Set9 and Suv39h1 histone methyltransferases is specific, as the methylation of H3-K9 by the histone methyltransferase G9a was not affected by Set9 methylation of H3-K4. Our studies suggest that Set9-mediated methylation of H3-K4 functions in transcription activation by competing with histone deacetylases and by precluding H3-K9 methylation by Suv39h1. Our results suggest that the methylation of histone tails can have distinct effects on transcription, depending on its chromosomal location, the combination of posttranslational modifications, and the enzyme (or protein complex) involved in the particular modification.
Papers of the Week Defining Histone-modifying Complexes
A variety of post-translational modifications of nucleosomal histones contribute to gene regulation. One such modification, methylation of histone H3 on lysine 4 (H3 K4), is associated with regions of active transcription. The yeast Set1-containing complex, COMPASS, was the first histone H3 K4 methyltransferase to be described. The mammalian Set1 homologue, MLL, also exists in a COMPASS-like complex that methylates H3 K4. Although there is only one Set1 in yeast, there are several MLL-related proteins in higher eukaryotic organisms. The MLL family of histone methyltransferases plays a key role in the regulation of gene expression and is an important regulator of developmental processes in metazoa. Despite intense interest the composition of MLL complexes has remained controversial. In this Paper of the Week, Young-Wook Cho and colleagues have defined MLL complexes and, in the process, have largely resolved controversies over the nature of the complexes. They show that complexes containing different MLL family members contain a COMPASS-like backbone but distinct sets of proteins specific to each version of MLL. In particular, their data indicate that MLL3 and MLL4 complexes include a submodule that includes PTIP, a protein that has been implicated in the response to DNA damage but whose biochemical function has remained unclear. See referenced article,
Genome-wide Map of Nucleosome Acetylation and Methylation in Yeast
Cell, 2005
Eukaryotic genomes are packaged into nucleosomes whose position and chemical modification state can profoundly influence regulation of gene expression. We profiled nucleosome modifications across the yeast genome using chromatin immunoprecipitation coupled with DNA microarrays to produce high-resolution genome-wide maps of histone acetylation and methylation. These maps take into account changes in nucleosome occupancy at actively transcribed genes and, in doing so, revise previous assessments of the modifications associated with gene expression. Both acetylation and methylation of histones are associated with transcriptional activity, but the former occurs predominantly at the beginning of genes, whereas the latter can occur throughout transcribed regions. Most notably, specific methylation events are associated with the beginning, middle, and end of actively transcribed genes. These maps provide the foundation for further understanding the roles of chromatin in gene expression and genome maintenance. (1999). NuA4, an essential transcription adaptor/histone H4 acetyltransferase complex containing Esa1p and the ATM-related cofactor Tra1p. EMBO J. 18, 5108-5119. Arndt, K., and Fink, G.R. (1986). GCN4 protein, a positive transcription factor in yeast, binds general control promoters at all 5# TGACTC 3# sequences. Proc. Natl. Acad. Sci. USA 83, 8516-8520. Bannister, A.J., Schneider, R., Myers, F.A., Thorne, A.W., Crane-Robinson, C., and Kouzarides, T. (2005). Spatial distribution of diand tri-methyl lysine 36 of histone H3 at active genes.