Active chromatin and noncoding RNAs: An intimate relationship

Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, United States.
Current opinion in genetics & development (Impact Factor: 7.57). 12/2011; 22(2):172-8. DOI: 10.1016/j.gde.2011.11.002
Source: PubMed


Eukaryotic genomes are packaged into chromatin, where diverse histone modifications can demarcate chromatin domains that facilitate or block gene expression. While silent chromatin has been associated with long noncoding RNAs (lncRNAs) for some time, new studies suggest that noncoding RNAs also modulate the active chromatin state. Divergent, antisense, and enhancer-like intergenic noncoding RNAs can either activate or repress gene expression by altering histone H3 lysine 4 methylation. An emerging class of enhancer-like lncRNAs may link chromosome structure to chromatin state and establish active chromatin domains. The confluence of several new technologies promises to rapidly expand this fascinating topic of investigation.

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Available from: Ryan Alexander Flynn, Sep 30, 2015
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    • "In addition, a large fraction of TSS-proximal transcriptional expenditure is dedicated to the production of unstable non-coding RNAs that are subject to RNA exosomemediated degradation (PROMPTs, uaRNAs, xTSS-RNAs) (Flynn et al., 2011; Pefanis et al., 2014; Preker et al., 2008). Although the characteristics of these new RNA species may overlap, it is abundantly clear that these non-coding RNAs function in the regulation of transcription initiation and transcription elongation by various mechanisms, including control of RNA polII pausing and recruitment of chromatin modification factors (Flynn and Chang, 2012; Reyes-Turcu and Grewal, 2012; Shin et al., 2013). "
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    ABSTRACT: We have ablated the cellular RNA degradation machinery in differentiated B cells and pluripotent embryonic stem cells (ESCs) by conditional mutagenesis of core (Exosc3) and nuclear RNase (Exosc10) components of RNA exosome and identified a vast number of long non-coding RNAs (lncRNAs) and enhancer RNAs (eRNAs) with emergent functionality. Unexpectedly, eRNA-expressing regions accumulate R-loop structures upon RNA exosome ablation, thus demonstrating the role of RNA exosome in resolving deleterious DNA/RNA hybrids arising from active enhancers. We have uncovered a distal divergent eRNA-expressing element (lncRNA-CSR) engaged in long-range DNA interactions and regulating IgH 3' regulatory region super-enhancer function. CRISPR-Cas9-mediated ablation of lncRNA-CSR transcription decreases its chromosomal looping-mediated association with the IgH 3' regulatory region super-enhancer and leads to decreased class switch recombination efficiency. We propose that the RNA exosome protects divergently transcribed lncRNA expressing enhancers by resolving deleterious transcription-coupled secondary DNA structures, while also regulating long-range super-enhancer chromosomal interactions important for cellular function. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 04/2015; 161(4):774-789. DOI:10.1016/j.cell.2015.04.034 · 32.24 Impact Factor
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    • "lncRNAs are able to activate or repress gene expression at multiple levels through diverse mechanisms. For example, lncRNAs can recruit repressive (e.g., PRC2) and activating (e.g., the Trithorax group) chromatin modifiers at the DNA level much like molecular scaffolds , leading to regulation of target gene expression [26] [27] [28] [29]. At the RNA level, lncRNAs play a role in post-transcriptional events during gene expression and contribute to splicing, mRNA translation and mRNA degradation [30] [31] [32] [33]. "
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    ABSTRACT: Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) hold immense prom ise for regenerative medicine due to their abilities to self-renew and to differentiate into all cell types. This unique property is controlled by a complex interplay between transcriptional factors and epigenetic regulators. Recent research indicates that the epigenetic role of non-coding RNAs (ncRNAs) is an integral component of this regulatory network. This report will summarize findings that focus on two classes of regulatory ncRNAs, microRNAs (miRNAs) and long ncRNAs (lncRNAs), in the induction, maintenance and directed differentiation of ESCs and iPSCs. Manipulating these two important types of ncRNAs would be crucial to unlock the therapeutic and research potential of pluripotent stem cells.
    10/2013; 11(5). DOI:10.1016/j.gpb.2013.09.004
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    • "It has been proposed that active enhancers may also be promoters regulating noncoding RNA expression in addition to their enhancer function [30,31]. Recent studies propose that eRNAs bind transcriptional co-activators and chromatin modifying complexes, mediate chromatin looping of enhancer elements with promoters in cis, and provide a structural scaffold for factors that regulate chromatin and gene expression [25,26,29]. Alternatively, the eRNAs might result from collisions of RNAPII with genomic regions or RNAPII interactions during long distance looping of enhancers to promoters [32]. "
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    ABSTRACT: The miR-200b~200a~429 gene cluster is a key regulator of EMT and cancer metastasis, however the transcription-based mechanisms controlling its expression during this process are not well understood. We have analyzed the miR-200b~200a~429 locus for epigenetic modifications in breast epithelial and mesenchymal cell lines using chromatin immunoprecipitation assays and DNA methylation analysis. We discovered a novel enhancer located approximately 5.1kb upstream of the miR-200b~200a~429 transcriptional start site. This region was associated with the active enhancer chromatin signature comprising H3K4me1, H3K27ac, RNA polymerase II and CpG dinucleotide hypomethylation. Luciferase reporter assays revealed the upstream enhancer stimulated the transcription of the miR-200b~200a~429 minimal promoter region approximately 27-fold in breast epithelial cells. Furthermore, we found that a region of the enhancer was transcribed, producing a short, GC-rich, mainly nuclear, non-polyadenylated RNA transcript designated miR-200b eRNA. Over-expression of miR-200b eRNA had little effect on miR-200b~200a~429 promoter activity and its production did not correlate with miR-200b~200a~429 gene expression. While additional investigations of miR-200b eRNA function will be necessary, it is possible that miR-200b eRNA may be involved in the regulation of miR-200b~200a~429 gene expression and silencing. Taken together, these findings reveal the presence of a novel enhancer, which contributes to miR-200b~200a~429 transcriptional regulation in epithelial cells.
    PLoS ONE 09/2013; 8(9):e75517. DOI:10.1371/journal.pone.0075517 · 3.23 Impact Factor
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