Short RNAs Are Transcribed from Repressed Polycomb Target Genes and Interact with Polycomb Repressive Complex-2

Kanhere, Aditi; Viiri, Keijo; Araújo, Carla Cavalcante; Rasaiyaah, Jane; Bouwman, Russell D.; Whyte, Warren A.; Pereira, Carlos Filipe; Brookes, Emily; Walker, Kimberly A.; Bell, George W.; Pombo, Ana; Fisher, Amanda G.; Young, Richard A.; Jenner, Richard G.

doi:10.1016/j.molcel.2010.03.019

Cited by 344 publications

(355 citation statements)

References 37 publications

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“…Indeed, 414 lincRNAs in our catalog stand out as located within intergenic regions associated with common disease. Future work will be necessary to identify RNA sequence domains that relate to function (Zhao et al 2008;Kanhere et al 2010), and to further classify lincRNAs into families. Our panorama of lincRNA properties will greatly advance these goals.…”

Section: Discussionmentioning

confidence: 99%

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Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses

Cabili¹,

Trapnell²,

Goff³

et al. 2011

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Large intergenic noncoding RNAs (lincRNAs) are emerging as key regulators of diverse cellular processes. Determining the function of individual lincRNAs remains a challenge. Recent advances in RNA sequencing (RNA-seq) and computational methods allow for an unprecedented analysis of such transcripts. Here, we present an integrative approach to define a reference catalog of >8000 human lincRNAs. Our catalog unifies previously existing annotation sources with transcripts we assembled from RNA-seq data collected from~4 billion RNA-seq reads across 24 tissues and cell types. We characterize each lincRNA by a panorama of >30 properties, including sequence, structural, transcriptional, and orthology features. We found that lincRNA expression is strikingly tissue-specific compared with coding genes, and that lincRNAs are typically coexpressed with their neighboring genes, albeit to an extent similar to that of pairs of neighboring protein-coding genes. We distinguish an additional subset of transcripts that have high evolutionary conservation but may include short ORFs and may serve as either lincRNAs or small peptides. Our integrated, comprehensive, yet conservative reference catalog of human lincRNAs reveals the global properties of lincRNAs and will facilitate experimental studies and further functional classification of these genes.

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Section: Discussionmentioning

confidence: 99%

“…These may be either by-products of chromatin remodeling and recruitment of the transcription machinery to the neighboring gene's promoter or functional transcripts (Kanhere et al 2010). Due to limited read length and computational methods, previous studies did not determine whether these transcripts are spliced.…”

Section: Divergently Transcribed Lincrnasmentioning

confidence: 99%

Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses

Cabili¹,

Trapnell²,

Goff³

et al. 2011

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“…In both hypothesis, the PRC2 activity on histone 3 may involve intermediates, such as proteins or non-coding RNAs that may target PRC2 to the À 2.1 to À 1.1 kb region on DNA. As noncoding RNAs interact with PRC2 at repressed genes 51,52 and because Spi-1 binds to RNA, 53 it is tempting to speculate that Spi-1 may affect PRC2 repressive activity or maintain PRC2 at the Bim promoter through its RNA-binding activity. In conclusion, our results provide evidence that a transcription factor can modulate the activity of PRC2 and epigenetic regulation without recruiting PRC2 at the site of its activity on the chromatin.…”

Section: α-Suz12mentioning

confidence: 99%

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

et al. 2013

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Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression. Cell Death and Differentiation (2013) 20, 1268-1278; doi:10.1038/cdd.2013.88; published online 12 July 2013Acute myeloid leukaemia (AML) develops through a multistep process driven by the progressive accumulation of mutations, leading to deregulation of cell proliferation and differentiation. Most frequently, abnormalities in cell differentiation are the result of loss-of-function mutations in lineage-specific transcription factors, whereas alterations in cell proliferation are associated with gain-of-function mutations in signalling pathways. 1 Mutations that target components of the spliceosomal machinery 2 and epigenetic regulators 3 have been identified as well, although their functional consequences in leukaemogenesis are not clear. To date, AML treatments are largely determined by the nature of the identified mutated proteins and a major challenge is to design molecules that can target each molecular alteration contributing to transformation. For that, understanding the molecular mechanisms controlled by an oncoprotein is one essential step. We have previously described a mouse model of erythroleukaemia (Spi-1 transgenic mice) that recapitulates the multistep development of human AML. 4 Spi-1 is a master transcription factor of haematopoiesis that is also involved in pre-mRNA splicing regulation. 5 During the preleukaemic stage of the disease, the differentiation blockage of the erythroid progenitors is the first oncogenic mark assoc...

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“…Besides its contributions to the core PRC2, there is also evidence that SUZ12 mediates interactions with the PRC2 cofactor JARID2 [18,21] . Moreover, SUZ12 is the PRC2 subunit with the strongest affinity for a set of noncoding RNAs (ncRNAs) from the 5′ ends of repressed target genes [18,22] .…”

Section: Introductionmentioning

confidence: 99%

“…Several recent reports suggest that lncRNAs play an important role in gene silencing and PRC2 recruitment to selective loci [22,33,38,[57][58][59][60][61][62][63][64][65][66][67] . For instance, PRC2 and H3K27me3 accumulate on the inactive X chromosome during X inactivation.…”

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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Short RNAs Are Transcribed from Repressed Polycomb Target Genes and Interact with Polycomb Repressive Complex-2

Cited by 344 publications

References 37 publications

Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses

Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

Structure of the PRC2 complex and application to drug discovery

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