Promiscuous RNA binding by Polycomb repressive complex 2
01 Nov 2013-Nature Structural & Molecular Biology (Nature Publishing Group)-Vol. 20, Iss: 11, pp 1250-1257
TL;DR: These findings support a model in which PRC2's promiscuous binding to RNA transcripts allows it to scan for target genes that have escaped repression, thus leading to maintenance of the repressed state.
Abstract: Polycomb repressive complex 2 (PRC2) is a histone methyltransferase required for epigenetic silencing during development and cancer, and it can be recruited to chromatin by long noncoding RNAs. In vitro binding studies and comparative analysis of genome-wide in vivo data now suggest a model for the maintenance of the repressed chromatin state by PRC2, directed by PRC2's promiscuous binding to nascent RNA transcripts.
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01 Jan 2011
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.
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TL;DR: The strategies that led to the identification of cancer-related lncRNAs and the methodologies and challenges involving the study of these molecules are discussed, as well as the imminent applications of these findings to the clinic.
Abstract: It is increasingly evident that many of the genomic mutations in cancer reside inside regions that do not encode proteins. However, these regions are often transcribed into long noncoding RNAs (lncRNAs). The recent application of next-generation sequencing to a growing number of cancer transcriptomes has indeed revealed thousands of lncRNAs whose aberrant expression is associated with different cancer types. Among the few that have been functionally characterized, several have been linked to malignant transformation. Notably, these lncRNAs have key roles in gene regulation and thus affect various aspects of cellular homeostasis, including proliferation, survival, migration or genomic stability. This review aims to summarize current knowledge of lncRNAs from the cancer perspective. It discusses the strategies that led to the identification of cancer-related lncRNAs and the methodologies and challenges involving the study of these molecules, as well as the imminent applications of these findings to the clinic.
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TL;DR: The pathway of ncRNA research is described, where every established "rule" seems destined to be overturned.
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Cites background from "Promiscuous RNA binding by Polycomb..."
...Promiscuous binding of PRC2 to thousands of RNAs has been suggested to allow it to survey for genes that have escaped repression and then to restore the repressed state (Davidovich et al., 2013)....
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TL;DR: A central role for RNA in human evolution and ontogeny is suggested and the emergence of the previously unsuspected world of regulatory RNA from a historical perspective is reviewed.
Abstract: Discoveries over the past decade portend a paradigm shift in molecular biology. Evidence suggests that RNA is not only functional as a messenger between DNA and protein but also involved in the regulation of genome organization and gene expression, which is increasingly elaborate in complex organisms. Regulatory RNA seems to operate at many levels; in particular, it plays an important part in the epigenetic processes that control differentiation and development. These discoveries suggest a central role for RNA in human evolution and ontogeny. Here, we review the emergence of the previously unsuspected world of regulatory RNA from a historical perspective.
1,112 citations
TL;DR: A method to purify a lncRNA from cells and identify proteins interacting with it directly using quantitative mass spectrometry is developed and it is shown that SHARP, which interacts with the SMRT co-repressor that activates HDAC3, is not only essential for silencing, but is also required for the exclusion of RNA polymerase II from the inactive X.
Abstract: Many long non-coding RNAs (lncRNAs) affect gene expression, but the mechanisms by which they act are still largely unknown. One of the best-studied lncRNAs is Xist, which is required for transcriptional silencing of one X chromosome during development in female mammals. Despite extensive efforts to define the mechanism of Xist-mediated transcriptional silencing, we still do not know any proteins required for this role. The main challenge is that there are currently no methods to comprehensively define the proteins that directly interact with a lncRNA in the cell. Here we develop a method to purify a lncRNA from cells and identify proteins interacting with it directly using quantitative mass spectrometry. We identify ten proteins that specifically associate with Xist, three of these proteins--SHARP, SAF-A and LBR--are required for Xist-mediated transcriptional silencing. We show that SHARP, which interacts with the SMRT co-repressor that activates HDAC3, is not only essential for silencing, but is also required for the exclusion of RNA polymerase II (Pol II) from the inactive X. Both SMRT and HDAC3 are also required for silencing and Pol II exclusion. In addition to silencing transcription, SHARP and HDAC3 are required for Xist-mediated recruitment of the polycomb repressive complex 2 (PRC2) across the X chromosome. Our results suggest that Xist silences transcription by directly interacting with SHARP, recruiting SMRT, activating HDAC3, and deacetylating histones to exclude Pol II across the X chromosome.
864 citations
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Availability: http://samtools.sourceforge.net
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