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. 2013 Jan 1;8(1):10–15. doi: 10.4161/epi.23333

reSETting chromatin during transcription elongation

Michaela Smolle 1, Jerry L Workman 1, Swaminathan Venkatesh 1,*
PMCID: PMC3549872  PMID: 23257840

Abstract

Maintenance of ordered chromatin structure over the body of genes is vital for the regulation of transcription. Increased access to the underlying DNA sequence results in the recruitment of RNA polymerase II to inappropriate, promoter-like sites within genes, resulting in unfettered transcription. Two new papers show how the Set2-mediated methylation of histone H3 on Lys36 (H3K36me) maintains chromatin structure by limiting histone dynamics over gene bodies, either by recruiting chromatin remodelers that preserve ordered nucleosomal distribution or by lowering the binding affinity of histone chaperones for histones, preventing their removal.

Keywords: chromatin, chromatin remodeling, histone acetylation, histone deacetylation, histone methyltransferase

Introduction

Under physiological conditions chromatin represents a strong barrier to transcription by RNA polymerase II (RNAP II).1,2 For transcription to take place in a controlled fashion, RNAP II has to move through the nucleosomal template. This process requires extensive modulation of chromatin structure through the remodeling and/or removal of existing nucleosomes and it is achieved through the concerted actions of chromatin remodelers,3 histone modifying enzymes4 and histone chaperones.5

At gene promoters, high turnover of histones is promoted by high levels of histone acetylation and the incorporation of the histone variant H2A.Z, thought to reduce nucleosome affinity for DNA and nucleosome stability, respectively. These measures result in the formation of a nucleosome-depleted region (NDR) that favors binding of transcription factors and formation of RNAP II pre-initiation complexes. In contrast, over gene bodies the original chromatin structure has to be restored once RNAP II has passed. Otherwise, promoter-like sequences within gene bodies become exposed, leading to inappropriate initiation from these sites and the production of so-called cryptic (or internally-initiated) transcripts both in the sense and antisense directions. One of the key pathways involved in suppressing these internally initiated transcripts in a co-transcriptional manner is the Set2/Rpd3S pathway.

Set2/Rpd3S Pathway

Set2 is a lysine methyltransferase (KMTase) that methylates histone H3 at the K36 residue. Set2 specifically associates with the Ser-2 phosphorylated form of the elongating RNAP II (Fig. 1A),6-9 that targets its KMTase activity toward the promoter distal ends of genes (Fig. 1B).10,11 While H3K36 methylated nucleosomes are enriched over transcribed genes,9,12 this modification nevertheless fulfills a repressive function. Previous work has shown that the RNAP II-associated Rpd3S histone deacetylase complex requires H3K36 methylation for efficient deacetylation of histones.13-17 Recognition of di- and trimethylated H3K36 through its Eaf3 and Rco1 subunits is required for Rpd3S catalytic activity, ensuring that coding regions remain hypoacetylated (Fig. 1A). Thus, Set2 mediated H3K36 methylation acts as a signal from the elongating RNAP II to target the deacetylase activity of Rpd3S toward the 3′ ends of genes. In the absence of Set2, H3K36 methylation or Rpd3S, co-transcriptionally acetylated histones accumulate on coding regions leading to transcription initiation from internal, cryptic promoters.15,18 The hyperacetylation of histones upon loss of Set2 was shown to depend on gene length and its rate of transcription. In particular, 3′ half of long genes and infrequently transcribed genes showed the maximal accumulation of acetylated histones over the coding regions (Fig. 1B).18 This observation can be explained by the fact that Ser-2 phosphorylation of RNAP II C-terminal domain (CTD) peaks after the first 500 bases of the coding region are transcribed. Consequently, Set2-mediated H3K36 methylation is targeted to nucleosomes from the mid to the 3′ end of genes, thereby defining the region over which the Set2/Rpd3S pathway acts. This leaves the question as to what pathway targets deacetylases to the 5′ end of genes. Recently, it has been shown that H3K4 di-methylation is necessary to target the deacetylase activity of the Set3 complex at the 5′ end of genes,19 in a manner analogous to the Set2/Rpd3S pathway.

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Figure 1. Set2-mediated H3K36 methylation and its functional consequences.(A) Set2/Rpd3S pathway. The RNAP II-associated histone methyltransferase Set2 methylates H3K36 (red circle). This mark is recognized by the Rco1 and Eaf3 subunits of the Rpd3S deacetylase complex that maintains genomic regions in a hypoacetylated state by removing acetyl marks (green circle). The arrow indicates the direction of transcription. (B) Distribution of H3K36 methylation (H3K36me), histone exchange and histone acetylation in wild-type or SET2 deleted (set2Δ) yeast strains. (C) Mechanism of Set2-mediated suppression of histone exchange. (i) Co-transcriptional methylation of H3K36 by Set2, results in (ii) preventing Asf1-mediated assembly of newly synthesized pre-acetylated histones (yellow cylinder). (iii) H3K36 methylated nucleosomes are targeted either by the Isw1b complex, or by the RNAP II-associated Chd1 remodeler, resulting in nucleosome remodeling in cis, thus allowing passage of RNAP II and preventing trans-histone exchange by Asf1. (iv) The Rpd3S deacetylase complex is targeted by H3K36 methylation to the coding regions, which is maintained in a hypoacetylated state. (v) The histone chaperone function of Rpd3S may be instrumental in the capture of H3K36 methylated histones and its reassembly following the passage of RNAP II.

Methylation of H3K36 Suppresses Histone Exchange

During chromatin transcription in metazoans, histone exchange occurs over gene bodies whereby histone H3 is replaced by variant H3.3,20,21 in a manner dependent on transcription rates.22,23 In yeast, histone exchange normally occurs over the 5′ and 3′ ends of genes (Fig. 1B), while histones over coding regions are replaced less frequently.24,25 In contrast to highly transcribed genes, low transcribed genes do not demonstrate much histone H3 exchange over the coding regions.25,26 However, these genes do exhibit a rapid and continuous exchange of H2A-H2B dimers by histone chaperones over the coding regions, which has been shown to be sufficient for RNAP II elongation.27,28 Interestingly, these infrequently transcribed genes are dependent on the Set2/Rpd3S co-transcriptional deacetylation pathway to regulate histone acetylation over coding regions.18 This observation led to the question whether H3K36 methylation had an additional role in the regulation of histone exchange over coding regions?

Using a specialized yeast strain that allows us to differentiate between “old” and “new” histone H3,26 we can monitor the sites of incorporation for new, soluble histone H3 in response to gene transcription and compare them to genomic loci that preferentially retain existing nucleosomes. In wild-type yeast cells, promoter regions showed maximal accumulation of new histones, while the coding regions retain their existing nucleosomes. Deletion of SET2 in this strain resulted in the increased accumulation of “new” histones over the coding region of genes (Fig. 1B). This confirmed our hypothesis that Set2-mediated H3K36 methylation indeed suppresses trans-histone exchange over the coding regions, particularly toward the 3′ ends of long genes.29 The ability of H3K36 methylated nucleosomes to prevent histone exchange could also explain why it suppresses internal initiation of transcription.

Co-transcriptional Hstone Acetylation is a Consequence of Histone Exchange

The loss of Set2-mediated H3K36 methylation results in increased histone exchange over coding regions, leading to the enrichment of histone acetylation (Fig. 1B). Perturbing the histone exchange pathway (by deleting ASF1)25 in a SET2 deletion mutant reduced enrichment of histone acetylation over the coding regions.29 This result suggests that histone exchange is responsible for co-transcriptional acetylation, by replacing unacetylated histones with pre-acetylated histones from the soluble pool. However, it also raises the question whether histone exchange is the sole means of co-transcriptional acetylation? Interestingly, the deletion of ASF1 in a SET2 mutant decreases acetylation over the coding regions, but does not completely abolish it. This suggests that lysine acetyltransferase (KAT) complexes are also involved in acetylating nucleosomes over coding regions30 in addition to histone exchange. Therefore, we conclude that exchange is an important mechanism to bring in acetylated histones to a genomic region in addition to the targeted recruitment of the KAT complexes. However, the enrichment of acetylation does not always correlate with histone exchange. Histone exchange levels remain unaffected at the promoters despite loss of Set2, although histone acetylation is reduced compared with the wild type.29 We believe that this could be due to the removal of acetyl marks by a 5′ end specific deacetylase like the Set3 deacetylase complex.19 Interestingly, a recent report has shown that the levels of the Rpd3S specific subunit, Rco1 are greatly increased over the promoter in a SET2 deletion mutant.13The action of these deacetylase complexes could therefore explain the observed decrease in histone acetylation over the promoters upon loss of Set2.

A key question that arises at this point is by what mechanism Set2-mediated H3K36 methylation (Fig. 1Ci) prevents histone exchange over coding regions, thereby suppressing both the co-transcriptional acetylation of histones and internal initiation of transcription? In the following sections we discuss two possible mechanisms, both of which may not necessarily be independent of one another.

Methylation of H3K36 Prevents Binding of Histone Chaperones

Histone chaperones play a key role in the assembly and disassembly of nucleosomes. Several histone chaperones including Asf1,31 Spt632 and the Spt16-containing FACT complex33 have been shown to be involved in the regulation of transcription elongation. It has been suggested that histone chaperones play a role in the capture and reassembly of nucleosomes that are displaced during transcription elongation. Several studies have also pointed to the fact that histone chaperones may facilitate elongation by disassembling nucleosomes ahead of RNAP II. Interestingly, we found that methylation of H3K36 reduces the affinity of the Asf1 histone chaperone for histone H3 as judged from peptide binding studies.29 Asf1 is involved both in the deposition of newly synthesized, pre-acetylated histones onto the DNA during replication, as well as nucleosome disassembly over the promoters during transcription. The presence of the H3K36 methyl mark over coding regions presumably disfavors Asf1 binding, thereby ensuring the retention of existing histones over gene bodies (Fig. 1Cii). While H3K36 tri-methylation reduces the affinity of both Spt6 and Spt16 to bind modified histone H3, H3K36 di-methylation does not seem to affect the binding affinity. This observation is relevant as Spt6 is required to maintain nucleosomal integrity over coding regions,32 presumably over regions enriched for H3K36 di-methylation. Recent studies have indicated that the core subunits of the Rpd3 complex (Rpd3, Ume1 and Sin3) possess histone chaperone activity.34 This gives rise to the interesting possibility that in combination with Rco1 and Eaf3 subunits, the Rpd3 core subunits may act as a H3K36 methyl specific histone chaperone. Therefore, the Rpd3S complex would not only deacetylate nucleosomes methylated at H3K36, but also capture and reassemble the same histones that are displaced by the elongating RNAP II (Fig. 1Cv).

Methylation of H3K36 Recruits Chromatin Remodelers and Suppresses Histone Exchange

Remodeling factors use the energy generated from ATP hydrolysis to slide or evict nucleosomes, thus affecting chromatin organization. Interestingly, we found chromatin remodelers Isw1 and Chd1 associated with H3K36 methylated mononucleosomes isolated from yeast chromatin.12 Isw1, its homolog Isw2 and Chd1 fulfill partially redundant functions. An isw1Δ isw2Δ chd1Δ strain displays synthetic phenotypes35 as well as widespread disruption of nucleosome positioning throughout the yeast genome.36,37

Two distinct Isw1 complexes exist in yeast. Isw1 associates with Ioc3 or Ioc2 and Ioc4 to form two different remodeling complexes, Isw1a and Isw1b respectively, which are thought to target the remodelers to different genomic locations.38 Indeed, Ioc4 preferentially interacts with H3K36 methylated nucleosomes both in vitro and in vivo.39 It contains an N-terminal PWWP domain that preferentially binds trimethylated H3K36 nucleosomes. Deletion or mutation of the Ioc4 PWWP domain results in reduced nucleosome binding in vitro and in vivo.39,40 Similarly, deletion of SET2 abrogates Ioc4 localization to the bodies of genes genome-wide.39 Chd1 is not recruited directly to coding regions through H3K36 methylation either in vivo or in vitro.41,42 Instead, it interacts with RNAP II-associated factors such as the PAF complex and Spt5 and thus ensures localization to actively transcribed genes (Fig. 1Ciii).43-45

Using genome-wide ChIP-chip experiments we showed that both Isw1b and Chd1 play important and complementary roles in the retention of H3K36-methylated nucleosomes over ORFs. Deletion of either ISW1, IOC4 or CHD1 causes increased histone exchange over gene bodies.39,46 Simultaneously, these deletions also result in significant increases in histone acetylation over coding regions, while there is no or little change in H3K36me3 levels. These results suggest that the remodelers are able and required to retain hypoacetylated, H3K36 methylated nucleosomes over gene bodies.39 Catalytic activity is required for this process as an ISW1K227R catalytic mutant also resulted in increased histone exchange over coding regions.

Why are two different remodeling enzymes involved in the regulation of ORF chromatin structure? While Isw1 and Chd1 do have overlapping functions, it is important to note that they are also complimentary. The effect of ISW1 deletion on histone turnover was greatest over infrequently transcribed genes; the same set of genes that are also most reliant on Set2 for efficient regulation. In contrast, deletion of CHD1 increased histone exchange over both frequently and infrequently transcribed genes, in agreement with its purported recruitment through RNAP II-associated factors.

Regulation of Internally-Initiated Transcription

In contrast to other chromatin remodelers, the ISWI and CHD families of remodelers have generally been implicated in the repression rather than activation of gene transcription. However, deletion of either ISW1, ISW2 and/or CHD1 does not cause large-scale changes in gene transcription overall.39,47 Rather, deletion of ISW1 and CHD1 does result in the widespread production of both sense and antisense cryptic transcripts,39,48,49 in agreement with its proposed function in limiting histone turnover and acetylation over coding regions.39 In fact there is good overlap between the genes that exhibit cryptic transcription in an isw1Δ chd1Δ strain and those that display increased cryptic transcription and histone exchange in a set2Δ background.39 As expected, the remodelers function within the Set2 pathway as deletion of the remodelers in a set2Δ background does not result in further increases in either the levels of cryptic transcripts produced or histone acetylation observed over coding sequences. Thus, repression of cryptic transcription in wild-type yeast is achieved through the H3K36me-dependent suppression of histone exchange. Isw1b and Chd1 activities ensure the retention of existing, H3K36 methylated and hypoacetylated nucleosomes and disfavors trans-histone exchange (Fig. 1Ciii).

Conclusion

Histone exchange involves the replacement of existing nucleosomes with newly synthesized histones, resulting in the removal or dilution of preexisting histone modification marks. By preventing histone exchange, H3K36 methylation ensures their persistence following transcription elongation. H3K36 methylation behaves as a stable transcription memory mark, indicating the passage of RNAP II, which could be removed by either replication-coupled exchange or the targeted recruitment of specific demethylases. Using histone exchange to deliver histone acetylation ensures rapid delivery of the modification at a genome-wide scale. This feature could help regulate events like transcription and replication without depending on the targeted recruitment of the KAT complexes.

Set2-mediated H3K36 methylation uses multiple mechanisms, such as the targeted recruitment of chromatin remodelers and/or lowering the binding affinity for histone chaperones to prevent histone exchange over coding regions (Fig. 1C). Consequently, this process allows for the retention of existing histones over gene bodies, with the ultimate aim of suppressing internally-initiated transcripts. Recent data have shown that cryptic, non-coding transcripts may play a key role in the regulation of delicate biological processes such as sporulation.50 Interestingly, these studies suggest that the process of transcription, rather than the non-coding RNA themselves may be key in regulating gene expression.51

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Footnotes

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