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Cryptic RNA-binding by PRC2 components EZH2 and SUZ12.

ABSTRACT: Polycomb repressive complex 2 (PRC2) is a histone-modifying complex that di/tri-methylates histone H3 lysine 27 (H3K27), a mark of transcriptionally repressed chromatin. However, how PRC2 is specifically recruited to its target loci remains controversial, although it has been postulated that long non-coding RNAs (lncRNAs) can function as guides. Here we purified individual components of PRC2 from human cultured cells and found that EZH2 and SUZ12 can directly bind to RNAs. In agreement with recent evidence, our results support the notion that these two PRC2 subunits have RNA-binding activity, with general preference for longer RNAs. However, the length alone does not explain their cryptic substrate preference. Our data highlight the difficulty of characterizing the RNA-binding activity of PRC2.

SUBMITTER: Betancur JG

PROVIDER: S-EPMC4615636 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Cryptic RNA-binding by PRC2 components EZH2 and SUZ12.

Betancur Juan G JG Tomari Yukihide Y

RNA biology 20150101 9

Polycomb repressive complex 2 (PRC2) is a histone-modifying complex that di/tri-methylates histone H3 lysine 27 (H3K27), a mark of transcriptionally repressed chromatin. However, how PRC2 is specifically recruited to its target loci remains controversial, although it has been postulated that long non-coding RNAs (lncRNAs) can function as guides. Here we purified individual components of PRC2 from human cultured cells and found that EZH2 and SUZ12 can directly bind to RNAs. In agreement with rece ...[more]

PMID: 26177152

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Project description:Distinctive patterns of chromatin modification control gene expression and define cellular identity during development and cell differentiation. Polycomb repressive complex 2 (PRC2), the sole mammalian enzymatic complex capable of establishing gene-repressive high-degree methylation of histone H3 at lysine 27 (H3K27), plays crucial roles in regulation of normal and malignant hematopoiesis. Recently, increasing evidence has indicated that recurrent gain-of-function mutation and overexpression of EZH2, the catalytic subunit of PRC2, drive and promote malignant transformation such as B-cell lymphomagenesis, providing a rationale for PRC2 inhibition as a novel anticancer strategy. Here, we summarize the recently developed strategies for inhibition of PRC2, which include a series of highly specific, highly potent, small-molecule inhibitors of EZH2 and EZH1, an EZH2-related methyltransferase. PRC2 establishes functional crosstalk with numerous epigenetic machineries during dynamic regulation of gene transcription. Perturbation of such functional crosstalk caused by genetic events observed in various hematologic cancers, such as inactivation of SNF5 and somatic mutation of UTX, confers PRC2 dependence, thus rendering an increased sensitivity to PRC2 inhibition. We discuss our current understanding of EZH2 somatic mutations frequently found in B-cell lymphomas and recurrent mutations in various other epigenetic regulators as novel molecular predictors and determinants of PRC2 sensitivity. As recent advances have indicated a critical developmental or tumor-suppressive role for PRC2 and EZH2 in various tissue types, we discuss concerns over potentially toxic or even adverse effects associated with EZH2/1 inhibition in certain biological contexts or on cancer genetic background. Collectively, inhibition of PRC2 catalytic activity has emerged as a promising therapeutic intervention for the precise treatment of a range of genetically defined hematologic malignancies and can be potentially applied to a broader spectrum of human cancers that bear similar genetic and epigenetic characteristics.

Dataset Information

Cryptic RNA-binding by PRC2 components EZH2 and SUZ12.

Publications

Cryptic RNA-binding by PRC2 components EZH2 and SUZ12.

Similar Datasets

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