Methylation of H3K4 Is Required for Inheritance of Active Transcriptional States

Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Current biology: CB (Impact Factor: 9.57). 02/2010; 20(5):397-406. DOI: 10.1016/j.cub.2010.01.017
Source: PubMed

ABSTRACT Maintenance of differentiation programs requires stability, when appropriate, of transcriptional states. However, the extent to which inheritance of active transcriptional states occurs from mother to daughter cells has not been directly addressed in unperturbed cell populations.
By live imaging of single-gene transcriptional events in individual cells, we have directly recorded the potential for mitotic inheritance of transcriptional states down cell lineages. Our data showed strong similarity in frequency of transcriptional firing between mother and daughter cells. This memory persisted for complete cell cycles. Both transcriptional pulse length and pulsing rate contributed to overall inheritance, and memory was determined by lineage, not cell environment. Analysis of transcription in chromatin mutants demonstrated that the histone H3K4 methylase Set1 and Ash2, a component of the methylase complex, are required for memory. The effects of Set1 methylation may be mediated directly by chromatin, because loss of memory also occurred when endogenous H3K4 was replaced by alanine. Although methylated H3K4 is usually associated with active transcriptional units, the modification was not required for gene activity but stabilized transcriptional frequency between generations.
Our data indicate that methylated H3K4 can act as a chromatin mark reflecting the original meaning of "epigenetic."

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    • "Post-translational modifications of histone proteins and DNA are two epigenetic mechanisms that modify gene expression. The information conveyed by these alterations is not encoded by the nucleotide sequence, but is heritable and can be transmitted, once established, to daughter cells and likely from generation to generation (Probst et al., 2009; Muramoto et al., 2010). The functional consequences of post-transcriptional modification of histones can be direct, causing structural changes to chromatin, or indirect, acting through the recruitment of effector proteins. "
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    ABSTRACT: Histone methylation is a conserved epigenetic mechanism in eukaryotes. Most of the histone lysine methyltransferases (HKMTases) conferring such modifications are proteins with a conserved SET domain responsible for enzymatic activity. Genetic studies in Arabidopsis thaliana have revealed that proteins from the Trithorax group (TrxG) are critical in activating transcription by methylating lysine 4 and lysine 36 of histone H3. Two TrxG proteins, ATXR3 and ATX1 (also called SET DOMAIN GROUP 2 and 27, respectively) are necessary for global genome-wide H3K4me3 deposition in Arabidopsis, whilst ASHH2 (also called SDG8) is a multi-functional enzyme with H3K4 and H3K36 methylation activity. Using phylogenetic analysis, we have identified the common bean (Phaseolus vulgaris L.) gene orthologs to Arabidopsis ATXR3, ASHH2, and ATX1 genes, which we have designated PvATXR3h, PvASHH2h, and PvTRX1h, respectively. Analysis of these genes with qRT-PCR reveals that all three are broadly expressed during plant and nodule development. Through a reverse genetics approach, we created common bean composite plants to knock-down PvATXR3h, PvTRX1h, and PvASHH2h expression. From analysis of the transgenic root phenotype, we conclude that transgenic root growth and development in the common bean was hindered by PvASHH2h gene downregulation.
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    • "may be required to maintain fully active gene expression. Experiments in Dictyostelium and Xenopus have also provided evidence that H3K4me3 is required to maintain fully active transcription through cell division (Ng & Gurdon, 2008; Muramoto et al, 2010). "
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    ABSTRACT: REV1-deficient chicken DT40 cells are compromised in replicating G quadruplex (G4)-forming DNA. This results in localised, stochastic loss of parental chromatin marks and changes in gene expression. We previously proposed that this epigenetic instability arises from G4-induced replication fork stalls disrupting the accurate propagation of chromatin structure through replication. Here, we test this model by showing that a single G4 motif is responsible for the epigenetic instability of the BU-1 locus in REV1-deficient cells, despite its location 3.5 kb from the transcription start site (TSS). The effect of the G4 is dependent on it residing on the leading strand template, but is independent of its in vitro thermal stability. Moving the motif to more than 4 kb from the TSS stabilises expression of the gene. However, loss of histone modifications (H3K4me3 and H3K9/14ac) around the transcription start site correlates with the position of the G4 motif, expression being lost only when the promoter is affected. This supports the idea that processive replication is required to maintain the histone modification pattern and full transcription of this model locus.
    The EMBO Journal 09/2014; 33(21). DOI:10.15252/embj.201488398 · 10.43 Impact Factor
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    • "Indeed, a growing body of work from across the eukaryotic divide associates the H3K4me3 mark with stable transcription. Using live imaging to follow transcription events at a single housekeeping gene in individual Dictyostelium cells, Muramoto et al. showed that frequency of transcriptional pulses tended to be inherited between successive cell generations, and that H3K4me3 marks were important in maintaining the memory of active states [39]. In a similar vein, diverse studies attribute to H3K4me3 a role in preserving and/or reflecting the characteristic expression profiles of differentiated cells. "
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    ABSTRACT: Various histone modifications are widely associated with gene expression, but their functional selectivity at individual genes remains to be characterized. Here, we identify widespread differences between genome-wide patterns of two prominent marks, H3K9ac and H3K4me3, in budding yeasts. As well as characteristic gene profiles, relative modification levels vary significantly amongst genes, irrespective of expression. Interestingly, we show that these differences couple to contrasting features: higher methylation to essential, periodically expressed, 'DPN' (Depleted Proximal Nucleosome) genes, and higher acetylation to non-essential, responsive, 'OPN' (Occupied Proximal Nucleosome) genes. Thus, H3K4me3 may generally associate with expression stability, and H3K9ac, with variability. To evaluate this notion, we examine their association with expression divergence between the closely related species, S. cerevisiae and S. paradoxus. Although individually well conserved at orthologous genes, changes between modifications are mostly uncorrelated, indicating largely non-overlapping regulatory mechanisms. Notably, we find that inter-species differences in methylation, but not acetylation, are well correlated with expression changes, thereby proposing H3K4me3 as a candidate regulator of expression divergence. Taken together, our results suggest distinct evolutionary roles for expression-linked modifications, wherein H3K4me3 may contribute to stabilize average expression, whilst H3K9ac associates with more indirect aspects such as responsiveness.
    PLoS ONE 07/2014; 9(7):e101538. DOI:10.1371/journal.pone.0101538 · 3.23 Impact Factor
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