Polycomb-like 2 Associates with PRC2 and Regulates Transcriptional Networks during Mouse Embryonic Stem Cell Self-Renewal and Differentiation

Walker, Emily M.; Chang, Wing Y.; Hunkapiller, Julie; Cagney, Gerard; Garcha, Kamal; Torchia, Joseph; Krogan, Nevan J.; Reiter, Jeremy F.; Stanford, William L.

doi:10.1016/j.stem.2009.12.014

Cited by 170 publications

(226 citation statements)

References 70 publications

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“…Promoter reads were counted from -2000 to +2000 relative to the transcription start site and normalized to reads per million (rpm). Following public data sets were used: SUZ12 (GSM700554, GSM700553), PHF19 (GSM700556, GSM700555) 10 , MTF2 (GSM415050) 12 , MRE-Seq (GSM881347) 29 , H3K4me3 (GSM2027596) 34 . CpG island and promoter definitions were downloaded from the UCSC browser.…”

Section: Methodsmentioning

confidence: 99%

“… a, Heatmap of MTF2 12 , PHF19 10 , unmethylated CpGs 29 and SUZ12 10 at three promoter groups: CpG island (CGI)-containing promoters enriched for SUZ12 (Group 1, n = 2,008), CGI-containing promoters with low SUZ12 (Group 2, n = 11,743) or promoters without CGI (Group 3, n = 13,117). b, Enriched DNA motifs at MTF2 and PHF19 bound locations.…”

Section: Figurementioning

confidence: 99%

“…PCL proteins have been proposed to be involved in recruiting PRC2 to chromatin 4,6,10,12,24 . Analysis of publically available data 10,12 demonstrated that MTF2 and PHF19 colocalize with PRC2 at a subset of unmethylated CpG island-containing promoters in mouse embryonic stem cells (mESCs, Fig.…”

mentioning

confidence: 99%

“…Analysis of publically available data 10,12 demonstrated that MTF2 and PHF19 colocalize with PRC2 at a subset of unmethylated CpG island-containing promoters in mouse embryonic stem cells (mESCs, Fig. 4a).…”

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Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

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The Polycomb repressive complex 2 (PRC2) mainly mediates transcriptional repression1,2 and plays essential roles in various biological processes including the maintenance of cell identity and proper differentiation. Polycomb-like proteins (PCLs), including PHF1, MTF2 and PHF19, are PRC2 associated factors that form sub-complexes with PRC2 core components3, and have been proposed to modulate PRC2’s enzymatic activity or its recruitment to specific genomic loci4–13. Mammalian PRC2 binding sites are enriched in CG content, which correlate with CpG islands that display a low level of DNA methylation14. However, the mechanism of PRC2 recruitment to CpG islands is not fully understood. In this study, we solved the crystal structures of the N-terminal domains of PHF1 and MTF2 with bound CpG-containing DNAs in the presence of H3K36me3-containing histone peptides. We found that the extended homologous (EH) regions of both proteins fold into a winged-helix structure, which specifically binds to the unmethylated CpG motif but in a manner completely different from the canonical winged-helix motif-DNA recognition. We further showed that the PCL EH domains are required for efficient recruitment of PRC2 to CpG island-containing promoters in mouse embryonic cells. Our research provides the first direct evidence demonstrating that PCLs are critical for PRC2 recruitment to CpG islands, thereby further clarifying their roles in transcriptional regulation in vivo.

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Section: Methodsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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confidence: 99%

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Polycomb-like proteins link the PRC2 complex to CpG islands

Liefke

Jiang

et al. 2017

Nature

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323

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“…Another feature worthy of attention is the ability of PHF1 to bind and protect p53 from MDM2-mediated ubiquitination and degradation [48] , implicating PHF1 in regulating cell growth arrest and apoptosis. MTF2/PCL2 function has been mainly analyzed in ES cells, where it is a component of biochemically distinct PRC2 com- plexes that it recruits to HOX genes and other target loci to regulate transcriptional networks during axial development [49,50] . Paradoxically, MTF2 is also involved in activating the CDKN2A gene and promotes cellular senescence [49] , suggesting that MTF2 might locally suppress the catalytic activity of PRC2.…”

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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Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies

et al. 2011

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Chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) have an inherent tendency to progress to acute myeloid leukemia (AML). Using high-resolution SNP microarrays, we studied a total of 517 MPN and MDS patients in different disease stages, including 77 AML cases with previous history of MPN (N 5 46) or MDS (N 5 31). Frequent chromosomal deletions of variable sizes were detected, allowing the mapping of putative tumor suppressor genes involved in the leukemic transformation process. We detected frequent deletions on the short arm of chromosome 6 (del6p). The common deleted region on 6p mapped to a 1.1-Mb region and contained only the JARID2 gene-member of the polycomb repressive complex 2 (PRC2). When we compared the frequency of del6p between chronic and leukemic phase, we observed a strong association of del6p with leukemic transformation (P 5 0.0033). Subsequently, analysis of deletion profiles of other PRC2 members revealed frequent losses of genes such as EZH2, AEBP2, and SUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses of JARID2 and AEBP2. We observed frequent codeletion of AEBP2 and ETV6, and similarly, SUZ12 and NF1. Using next generation exome sequencing of 40 patients, we identified only one somatic mutation in the PRC2 complex member SUZ12. As the frequency of point mutations in PRC2 members was found to be low, deletions were the main type of lesions targeting PRC2 complex members. Our study suggests an essential role of the PRC2 complex in the leukemic transformation of chronic myeloid disorders. Am. J. Hematol. 87:245-250, 2012. V

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Polycomb-like 2 Associates with PRC2 and Regulates Transcriptional Networks during Mouse Embryonic Stem Cell Self-Renewal and Differentiation

Cited by 170 publications

References 70 publications

Polycomb-like proteins link the PRC2 complex to CpG islands

Polycomb-like proteins link the PRC2 complex to CpG islands

Structure of the PRC2 complex and application to drug discovery

Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies

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