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Journal ArticleDOI

Transcriptional regulation by Polycomb group proteins.

TL;DR: The current knowledge of the PRC complexes is discussed, how they are targeted to chromatin and how the high diversity of the PcG proteins allows these complexes to influence cell identity.
Abstract: Polycomb group (PcG) proteins function within Polycomb repressive complexes (PRCs), which modify histones and other proteins and silence target genes. This Review highlights new insights into the role of PcG proteins in gene regulation, specifically in controlling self-renewal and differentiation of embryonic stem cells, and into how PRCs are targeted to chromatin.
Citations
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Journal ArticleDOI
TL;DR: This Review describes special events in the lifetimes of lncRNAs — before, during and after transcription — and discusses how these events ultimately shape the unique characteristics and functional roles of lNCRNAs.
Abstract: Long non-coding RNAs (lncRNAs) are a diverse class of RNAs that engage in numerous biological processes across every branch of life. Although initially discovered as mRNA-like transcripts that do not encode proteins, recent studies have revealed features of lncRNAs that further distinguish them from mRNAs. In this Review, we describe special events in the lifetimes of lncRNAs - before, during and after transcription - and discuss how these events ultimately shape the unique characteristics and functional roles of lncRNAs.

2,568 citations

Journal ArticleDOI
TL;DR: A unifying perspective is synthesized that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription.
Abstract: Recent genomic studies have resulted in an emerging understanding of the role of chromatin regulators in the development of cancer. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex, is recurrently mutated in several forms of cancer and is highly expressed in numerous others. Notably, both gain-of-function and loss-of-function mutations occur in cancers but are associated with distinct cancer types. Here we review the spectrum of EZH2-associated mutations, discuss the mechanisms underlying EZH2 function, and synthesize a unifying perspective that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription. We further discuss EZH2 inhibitors that are now showing early signs of promise in clinical trials and also additional strategies to combat roles of EZH2 in cancer.

1,047 citations

Journal ArticleDOI
TL;DR: The possible role of epigenetic abnormalities as well as genetic alterations in such dynamics and in the creation of cellular heterogeneity in cancers of all types are discussed.

752 citations


Cites background from "Transcriptional regulation by Polyc..."

  • ...In this view, the degree of the H3K27me3 occupancy builds by default when transcription is low (Di Croce and Helin, 2013)....

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Journal ArticleDOI
TL;DR: Key recent advances in the understanding of the epigenetic language encompassing histone and DNA modifications are highlighted and foreshadow challenges that lie ahead as the authors continue the quest to decipher the fundamental mechanisms of chromatin regulation.

618 citations


Cites methods from "Transcriptional regulation by Polyc..."

  • ...Applying this approach to H3K27me2 and H3K27me3 (marks of facultative heterochromatin written by the EZH2 subunit of the PRC2 complex [94]) as well as H4K20me1 (written by PR-Set7 and involved in the DNA damage response and mitotic chromatin condensation [95]), populations of symmetrically and asymmetrically modified nucleosomes were identified....

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Journal ArticleDOI
24 Sep 2015-Nature
TL;DR: The results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.
Abstract: Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced haematological malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9;Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.

422 citations

References
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Journal ArticleDOI
18 Sep 1997-Nature
TL;DR: The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it.
Abstract: The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it. Both histone/histone and histone/DNA interactions depend on the histone fold domains and additional, well ordered structure elements extending from this motif. Histone amino-terminal tails pass over and between the gyres of the DNA superhelix to contact neighbouring particles. The lack of uniformity between multiple histone/DNA-binding sites causes the DNA to deviate from ideal superhelix geometry.

7,841 citations

Journal ArticleDOI
18 May 2007-Cell
TL;DR: High-resolution maps for the genome-wide distribution of 20 histone lysine and arginine methylations as well as histone variant H2A.Z, RNA polymerase II, and the insulator binding protein CTCF across the human genome using the Solexa 1G sequencing technology are generated.

6,488 citations


"Transcriptional regulation by Polyc..." refers background in this paper

  • ...; and from the Novo Nordisk Foundation, the Danish Cancer Society and the Danish Council for Strategic Research (12-110503) to K....

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  • ...This work was supported by grants from the Spanish ‘Ministerio de Educación y Ciencia’ (BFU2010-18692) to L.D.C.; from European Commission’s 7th Framework Program 4DCellFate (grant number 277899) to L.D.C. and K.H.; and from the Novo Nordisk Foundation, the Danish Cancer Society and the Danish Council for Strategic Research (12-110503) to K.H. ComPetIng FInAnCIAL InteRests The authors declare no competing financial interests....

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Journal ArticleDOI
29 Jun 2007-Cell
TL;DR: The transcriptional landscape of the four human HOX loci is characterized at five base pair resolution in 11 anatomic sites and 231 HOX ncRNAs are identified that extend known transcribed regions by more than 30 kilobases, suggesting transcription of ncRNA may demarcate chromosomal domains of gene silencing at a distance.

4,003 citations


"Transcriptional regulation by Polyc..." refers background in this paper

  • ...; and from the Novo Nordisk Foundation, the Danish Cancer Society and the Danish Council for Strategic Research (12-110503) to K....

    [...]

  • ...This work was supported by grants from the Spanish ‘Ministerio de Educación y Ciencia’ (BFU2010-18692) to L.D.C.; from European Commission’s 7th Framework Program 4DCellFate (grant number 277899) to L.D.C. and K.H.; and from the Novo Nordisk Foundation, the Danish Cancer Society and the Danish Council for Strategic Research (12-110503) to K.H. ComPetIng FInAnCIAL InteRests The authors declare no competing financial interests....

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Journal ArticleDOI
07 Dec 1978-Nature
TL;DR: The wild-type and mutant segmentation patterns are consistent with an antero-posterior gradient in repressor concentration along the embryo and a proximo-distal gradient along the chromosome in the affinities for repressor of each gene's cis-regulatory element.
Abstract: The bithorax gene complex in Drosophila contains a minimum of eight genes that seem to code for substances controlling levels of thoracic and abdominal development. The state of repression of at least four of these genes is controlled by cis-regulatory elements and a separate locus (Polycomb) seems to code for a repressor of the complex. The wild-type and mutant segmentation patterns are consistent with an antero-posterior gradient in repressor concentration along the embryo and a proximo-distal gradient along the chromosome in the affinities for repressor of each gene's cis-regulatory element.

3,520 citations

Journal ArticleDOI
TL;DR: A model in which some lincRNAs guide chromatin-modifying complexes to specific genomic loci to regulate gene expression is proposed, and it is shown that siRNA-mediated depletion of certain linc RNAs associated with PRC2 leads to changes in gene expression.
Abstract: We recently showed that the mammalian genome encodes >1,000 large intergenic noncoding (linc)RNAs that are clearly conserved across mammals and, thus, functional. Gene expression patterns have implicated these lincRNAs in diverse biological processes, including cell-cycle regulation, immune surveillance, and embryonic stem cell pluripotency. However, the mechanism by which these lincRNAs function is unknown. Here, we expand the catalog of human lincRNAs to ≈3,300 by analyzing chromatin-state maps of various human cell types. Inspired by the observation that the well-characterized lincRNA HOTAIR binds the polycomb repressive complex (PRC)2, we tested whether many lincRNAs are physically associated with PRC2. Remarkably, we observe that ≈20% of lincRNAs expressed in various cell types are bound by PRC2, and that additional lincRNAs are bound by other chromatin-modifying complexes. Also, we show that siRNA-mediated depletion of certain lincRNAs associated with PRC2 leads to changes in gene expression, and that the up-regulated genes are enriched for those normally silenced by PRC2. We propose a model in which some lincRNAs guide chromatin-modifying complexes to specific genomic loci to regulate gene expression.

2,738 citations


"Transcriptional regulation by Polyc..." refers background in this paper

  • ...; and from the Novo Nordisk Foundation, the Danish Cancer Society and the Danish Council for Strategic Research (12-110503) to K....

    [...]

  • ...This work was supported by grants from the Spanish ‘Ministerio de Educación y Ciencia’ (BFU2010-18692) to L.D.C.; from European Commission’s 7th Framework Program 4DCellFate (grant number 277899) to L.D.C. and K.H.; and from the Novo Nordisk Foundation, the Danish Cancer Society and the Danish Council for Strategic Research (12-110503) to K.H. ComPetIng FInAnCIAL InteRests The authors declare no competing financial interests....

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