Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity

Pasini, Diego; Bracken, Adrian P.; Jensen, Michael Rugaard; Denchi, Eros Lazzerini; Helin, Kristian

doi:10.1038/sj.emboj.7600402

Cited by 816 publications

(764 citation statements)

References 30 publications

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“…(12,41). Previous studies have also shown that, although it contains the Su(var)3-9, enhancer of zeste, and trithorax domain for HMTase activity for H3K27, to gain catalytic activity EZH2 requires association with SUZ12 and EED (41). Therefore, the depletion of the PRC2 complex components due to treatment with HA-HDI or EZH2 siRNA results in the attenuation of HMTase activity of EZH2 and decreased trimethylation and dimethylation of H3K27 in the leukemia cells.…”

Section: Discussionmentioning

confidence: 98%

“…Total histone H3 levels were used as a loading control. (12,41). Previous studies have also shown that, although it contains the Su(var)3-9, enhancer of zeste, and trithorax domain for HMTase activity for H3K27, to gain catalytic activity EZH2 requires association with SUZ12 and EED (41).…”

Section: Discussionmentioning

confidence: 99%

“…Cells were lysed in 1Â hypotonic buffer, and nuclear extracts were prepared as described previously (40). To determine the HMTase activity, a previously described method was used (41). Five microgram of the nuclear extracts were combined with 2 AL of 5Â HMTase buffer [250 mmol/L Tris (pH 9.0), 2.5 mmol/L DTT, 5 mmol/L phenylmethylsulfonyl fluoride; Upstate], 0.55 ACi S-adenosyl-Lmethionine, 1 Ag recombinant histone H3, and diH 2 O up to 10 AL.…”

Section: Isolation Of Histonesmentioning

confidence: 99%

See 2 more Smart Citations

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

Fiskus¹,

Pranpat²,

Balasis³

et al. 2006

Molecular Cancer Therapeutics

103

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Human enhancer of zeste 2 (EZH2) protein belongs to the multiprotein polycomb repressive complex 2, which also includes suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). The polycomb repressive complex 2 complex possesses histone methyltransferase activity mediated by the Su(var)3-9, enhancer of zeste, and trithorax domain of EZH2, which methylates histone H3 on lysine (K)-27 (H3K27). In the present studies, we determined that treatment with the hydroxamate histone deacetylase inhibitor LBH589 or LAQ824 depleted the protein levels of EZH2, SUZ12, and EED in the cultured (K562, U937, and HL-60) and primary human acute leukemia cells. This was associated with decreased levels of trimethylated and dimethylated H3K27, with concomitant depletion of the homeobox domain containing HOXA9 and of MEIS1 transcription factors. Knockdown of EZH2 by EZH2 small interfering RNA also depleted SUZ12 and EED, inhibited histone methyltransferase activity, and reduced trimethylated and dimethylated H3K27 levels, with a concomitant loss of clonogenic survival of the cultured acute myelogenous leukemia (AML) cells. EZH2 small interfering RNA sensitized the AML cells to LBH589-mediated depletion of EZH2, SUZ12, and EED; loss of clonogenic survival; and LBH589-induced differentiation of the AML cells. These findings support the rationale to test anti-EZH2 treatment combined with hydroxamate histone deacetylase inhibitors as an antileukemia epigenetic therapy, especially against AML with coexpression of EZH2, HOXA9, and MEIS1 genes.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Isolation Of Histonesmentioning

confidence: 99%

See 1 more Smart Citation

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

Fiskus¹,

Pranpat²,

Balasis³

et al. 2006

Molecular Cancer Therapeutics

103

View full text Add to dashboard Cite

show abstract

“…[27][28][29][30][31] EZH2, a component of PRC2, is a histone methyltransferase that carries out the methylation of lysine 27 of histone H3. 32,33 Methylation of H3K27 recruits additional repressive complexes such as PRC1, which adds an additional level of repression that is propagated. 27,28,34,35 The DNA molecule can also be modified at the 5' position of cytosine rings present in CG dinucleotide sequences by addition of a methyl group.…”

Section: Metabolic Pathways and Mechanisms Of Regulationmentioning

confidence: 99%

The Epigenetics of Adult (Somatic) Stem Cells

Eilertsen

Floyd

Gimble

2008

Crit Rev Eukar Gene Expr

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While genetic studies have provided a wealth of information about health and disease, there is a growing awareness that individual characteristics are also determined by factors other than genetic sequences. These "epigenetic" changes broadly encompass the influence of the environment on gene regulation and expression and in a more narrow sense, describe the mechanisms controlling DNA methylation, histone modification and genetic imprinting. In this review, we focus on the epigenetic mechanisms that regulate adult (somatic) stem cell differentiation, beginning with the metabolic pathways and factors regulating chromatin structure and DNA methylation and the molecular biological tools that are currently available to study these processes. The role of these epigenetic mechanisms in manipulating adult stem cells is followed by a discussion of the challenges and opportunities facing this emerging field.

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“…SUZ12 is essential for the integrity of the PRC2 complexes, the stability of EZH2, and hence the HMTase activity of the complex [14,17] . It contains a C-terminal Vrn2-Emf2-Fis2-SUZ12…”

Section: Introductionmentioning

confidence: 99%

Structure of the PRC2 complex and application to drug discovery

et al. 2017

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The polycomb repressive complexes 2 (PRC2) complex catalyzes tri-methylation of histone H3 lysine 27 (H3K27), a repressive chromatin marker associated with gene silencing. Overexpression and mutations of PRC2 are found in a wide variety of cancers, making the catalytic activity of PRC2 an important target of cancer therapy. This review highlights recent structural breakthroughs of the human PRC2 complex bound to the H3K27 peptide and a small molecule inhibitor, which provide critically needed insight into PRC2-targeted drug discovery.

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Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity

Cited by 816 publications

References 30 publications

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

The Epigenetics of Adult (Somatic) Stem Cells

Structure of the PRC2 complex and application to drug discovery

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