Accurate H3K27 methylation can be established de novo by SUZ12-directed PRC2

Højfeldt, Jonas W.; Laugesen, Anne; Willumsen, Berthe M.; Damhofer, Helene; Hedehus, Lin; Tvardovskiy, Andrey; Mohammad, Faizaan; Jensen, Ole N.; Helin, Kristian

doi:10.1038/s41594-018-0036-6

Cited by 188 publications

(246 citation statements)

References 55 publications

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“…The deletions and inversion of the CTCF binding sites in STITCH led to the intermediate states ( Figure 4C and D). These results corroborate the well-established correlation of gene expression levels and the epigenetic states (Hosogane et al, 2016;Højfeldt et al, 2018;Narendra et al, 2015;Riising et al, 2014).…”

Section: The H3k27me3 Mark Reflects the Gene Expressionsupporting

confidence: 88%

Controlling gene activation by enhancers through a drug-inducible topological insulator

Tsujimura

Takase

Yoshikawa

et al. 2019

Preprint

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AbstractWhile regulation of gene-enhancer interaction is better understood, its application remains limited. Here, we reconstituted arrays of CTCF binding sites and devised a synthetic topological insulator with tetO for chromatin-engineering (STITCH). By coupling STITCH with tetR linked to the KRAB domain to induce heterochromatin and disable the insulation, we developed a drug-inducible system to control gene activation by enhancers. We applied this to dissect MYC regulation in human pluripotent stem cells. Insertion of STITCH between MYC and the enhancer down-regulated MYC and affected its target transcriptome. Progressive mutagenesis of STITCH led to preferential escalation of the gene-enhancer interaction, corroborating the strong insulation ability of STITCH. The STITCH insertion altered epigenetic states around MYC. Time-course analysis by drug induction uncovered deposition and removal of H3K27me3 repressive marks follows and reflects, but does not precede and determine, the expression change. Thus the tool provided important insights in gene regulation, demonstrating its potency.

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Section: The H3k27me3 Mark Reflects the Gene Expressionsupporting

confidence: 88%

Controlling gene activation by enhancers through a drug-inducible topological insulator

Tsujimura

Takase

Yoshikawa

et al. 2019

Preprint

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“…While we now have a good picture of the accessory subunits interacting with PRC2, their precise roles are only partially understood. This might be due to compensatory mechanisms, such that interfering both with PRC2.1 and PRC2.2 is required to inhibit PRC2 recruitment 19 as observed upon loss of SUZ12 20 .…”

Section: Theirmentioning

confidence: 99%

EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells

Ragazzini

Pérez-Palacios

Baymaz

et al. 2019

Preprint

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The Polycomb machinery is required for the proper orchestration of gene expression by virtue of its critical role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a new cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion of Ezhip leads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This alteration of the epigenetic content of mature oocytes does not affect the initial number of follicles but is associated with a reduction of follicles in aging mice. We provide evidences that mature oocytes Ezhip -/-are not fully functional and that fertility is strongly impaired in Ezhip -/-females. Altogether, our study uncovers EZHIP as a novel functional player in the comprehensive chromatin remodeling that occurs in the gonads.

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“…However, reintroduction of PRC2 into ESCs devoid of K27 methylation fully restore K27me3 landscape (Hojfeldt et al, 2018;Oksuz et al, 2018). This argues against a critical role for allosteric activation in establishment, but its importance in K27me3 maintenance remains debated.…”

Section: Introductionmentioning

confidence: 99%

Domain model explains propagation dynamics and stability of K27 and K36 methylation landscapes

Alabert

Loos

Völker-Albert

et al. 2019

Preprint

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Chromatin states must be maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications is central in this process. However, the histone modification landscape is challenged by incorporation of new unmodified histones during each cell cycle and the principles governing heritability remain unclear. Here, we take a quantitative computational modeling approach to describes propagation of K27 and K36 methylation states. We measure combinatorial K27 and K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones. Using model comparison, we reject active global demethylation and invoke the existence of domains defined by distinct methylation endpoints. We find that K27me3 on pre-existing histones stimulates the rate of de novo K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed, quantitative picture of the mutual antagonism between K27 and K37 methylation, and propose that it stabilizes epigenetic states across cell division.

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Accurate H3K27 methylation can be established de novo by SUZ12-directed PRC2

Cited by 188 publications

References 55 publications

Controlling gene activation by enhancers through a drug-inducible topological insulator

Controlling gene activation by enhancers through a drug-inducible topological insulator

EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells

Domain model explains propagation dynamics and stability of K27 and K36 methylation landscapes

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