Asymmetrically Modified Nucleosomes

Voigt, Philipp; LeRoy, Gary; Drury, William J.; Zee, Barry M.; Son, Jaesung; Beck, David B.; Young, Nicolas L.; Garcia, Benjamin A.; Reinberg, Danny

doi:10.1016/j.cell.2012.09.002

Cited by 377 publications

(477 citation statements)

References 42 publications

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“…S1), so the SDG8-ELF6 interaction is probably independent of transcriptional elongation. The mutually exclusive pattern between H3K27me3 and H3K36me3 has been found in several other systems (2,35,36) and could be explained by the observation that H3K36me3 can inhibit PRC2 activity (37). Our data here provide another possible explanation: that H3K36me3 antagonizes PRC2 repression by codelivering H3K27 demethylase activity with the H3K36 methyltransferase.…”

Section: Resultssupporting

confidence: 78%

Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC

Yang

Howard

Dean

2016

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

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Establishment and maintenance of gene expression states is central to development and differentiation. Transcriptional and epigenetic mechanisms interconnect in poorly understood ways to determine these states. We explore these mechanisms through dissection of the regulation of Arabidopsis thaliana FLOWERING LOCUS C (FLC). FLC can be present in a transcriptionally active state marked by H3K36me3 or a silent state marked by H3K27me3. Here, we investigate the trans factors modifying these opposing histone states and find a physical coupling in vivo between the H3K36 methyltransferase, SDG8, and the H3K27me3 demethylase, ELF6. Previous modeling has predicted this coupling would exist as it facilitates bistability of opposing histone states. We also find association of SDG8 with the transcription machinery, namely RNA polymerase II and the PAF1 complex. Delivery of the active histone modifications is therefore likely to be through transcription at the locus. SDG8 and ELF6 were found to influence the localization of each other on FLC chromatin, showing the functional importance of the interaction. In addition, both influenced accumulation of the associated H3K27me3 and H3K36me3 histone modifications at FLC. We propose the physical coupling of activation and derepression activities coordinates transcriptional activity and prevents ectopic silencing.epigenetic regulation | histone modifications | histone methyltransferase | histone demethylase | FLOWERING LOCUS C C hromatin-based transcriptional activity is particularly important in multicellular organisms, where cells differentiate into very different developmental states. Transcriptional states are induced by internal developmental signals or triggered by environmental conditions and are then epigenetically maintained through many cell divisions. Considerable evidence suggests that opposing histone modifications mark different transcriptional states (1-6). However, there is still great debate as to how histone-based transcriptional states are initially established and maintained through development (7,8). We used Arabidopsis FLOWERING LOCUS C (FLC) as a model gene to explore histone-based transcriptional regulation and epigenetic memory. Local chromatin states are critical for quantitatively controlling FLC expression (9). Active FLC expression requires functional FRIGIDA (FRI) and a set of histone modifying Trithorax homologs, Complex Proteins Associated with Set1 (COMPASS), RNA polymerase II Associated Factor 1 complex (PAF1C), and SET DOMAIN GROUP 8 (SDG8), the major H3K36 methyltransferase (10-17). Repression of FLC requires either the autonomous pathway, which coordinately influences transcriptional initiation and elongation with associated chromatin modulation, or vernalization, the cold-induced Polycomb silencing (18-21). Both of these involve accumulation of high levels of H3K27me3 at FLC (20-22). A series of FLC antisense transcripts (COOLAIR) contribute to these repression pathways (18,(23)(24)(25)(26) Opposing H3K36me3 and H3K27me3 states are particularly ...

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Section: Resultssupporting

confidence: 78%

Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC

Yang

Howard

Dean

2016

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

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“…Mitotic inheritance of H3K9 methylation does not require GLP's and G9a's methylation-spreading activity H3K9me2 occupies more than 30% of the genome (Lienert et al 2011;Voigt et al 2012) but can be rapidly reestablished during mitosis . Considering that G9a localizes at the replication foci (Esteve et al 2006) and G9a and GLP are activated by premethylated neighboring nucleosomes, it is very attractive to hypothesize that GLP and G9a may travel with the replication machinery and copy-paste H3K9 methylation from the parental nucleosomes to the newly deposited nucleosomes.…”

Section: H3k9 Methylation Promotes Glp's Enzymatic Activity Genes and Dmentioning

confidence: 99%

Recognition of H3K9 methylation by GLP is required for efficient establishment of H3K9 methylation, rapid target gene repression, and mouse viability

et al. 2015

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GLP and G9a are major H3K9 dimethylases and are essential for mouse early embryonic development. GLP and G9a both harbor ankyrin repeat domains that are capable of binding H3K9 methylation. However, the functional significance of their recognition of H3K9 methylation is unknown. Here, we report that the histone methyltransferase activities of GLP and G9a are stimulated by neighboring nucleosomes that are premethylated at H3K9. These stimulation events function in cis and are dependent on the H3K9 methylation binding activities of ankyrin repeat domains of GLP and G9a. Disruption of the H3K9 methylation-binding activity of GLP in mice causes growth retardation of embryos, ossification defects of calvaria, and postnatal lethality due to starvation of the pups. In mouse embryonic stem cells (ESCs) harboring a mutant GLP that lacks H3K9me1-binding activity, critical pluripotent genes, including Oct4 and Nanog, display inefficient establishment of H3K9me2 and delayed gene silencing during differentiation. Collectively, our study reveals a new activation mechanism for GLP and G9a that plays an important role in ESC differentiation and mouse viability.

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“…Enrichment between 50 and 100% indicates a mixed population (symmetric and asymmetric nucleosomes). Using a thoroughly vetted H4K20me1 antibody (which is an essential requirement for the analysis), roughly 50% of H4K20me1-containing nucleosomes are symmetric and 50% asymmetric (82). A future question of interest will be to test whether the different populations of H4K20me1 nucleosomes are linked to alternative pathways and functional outcomes as well as the mechanisms that result in one fate versus the other.…”

Section: Figmentioning

confidence: 99%

Histone H4 Lysine 20 (H4K20) Methylation, Expanding the Signaling Potential of the Proteome One Methyl Moiety at a Time

Nuland

Gozani

2016

Molecular & Cellular Proteomics

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Covalent post-translational modifications (PTMs) of proteins can regulate the structural and functional state of a protein in the absence of primary changes in the underlying sequence. Common PTMs include phosphorylation, acetylation, and methylation. Histone proteins are critical regulators of the genome and are subject to a highly abundant and diverse array of PTMs. To highlight the functional complexity added to the proteome by lysine methylation signaling, here we will focus on lysine methylation of histone proteins, an important modification in the regulation of chromatin and epigenetic processes. We review the signaling pathways and functions associated with a single residue, H4K20, as a model chromatin and clinically important mark that regulates biological processes ranging from the DNA damage response and DNA replication to gene expression and silencing. Molecular

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Asymmetrically Modified Nucleosomes

Cited by 377 publications

References 42 publications

Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC

Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC

Recognition of H3K9 methylation by GLP is required for efficient establishment of H3K9 methylation, rapid target gene repression, and mouse viability

Histone H4 Lysine 20 (H4K20) Methylation, Expanding the Signaling Potential of the Proteome One Methyl Moiety at a Time

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