RNA regulation of epigenetic processes

Mattick, John S.; Amaral, Paulo; Dinger, Marcel E.; Mercer, Tim R.; Mehler, Mark F.

doi:10.1002/bies.080099

Cited by 331 publications

(252 citation statements)

References 120 publications

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“…1C). In the post-genomics era it is now clear that the majority of transcription produces non-coding transcripts, many of which have been linked to the epigenetic control of gene expression (e.g long non-coding RNAs [89][90][91] or miRNAs targeting gene promoters [92][93][94] , Fig. 1C).…”

Section: Cross-regulation Of Mirnas and Epigenetic Mechanismsmentioning

confidence: 99%

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

2013

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The most fundamental roles of non-coding RNAs (ncRNAs) and epigenetic mechanisms are the guidance of cellular differentiation in development and the regulation of gene expression in adult tissues. In brain, both ncRNAs and the various epigenetic gene regulatory mechanisms play a fundamental role in neurogenesis and normal neuronal function. Thus, epigenetic chromatin remodelling can render coding sites transcriptionally inactive by DNA methylation, histone modifications or antisense RNA interactions. On the other hand, microRNAs (miRNAs) are ncRNA molecules that can regulate the expression of hundreds of genes post-transcriptionally, typically recognising binding sites in the 3′ untranslated region (UTR) of mRNA transcripts. Furthermore, there are a myriad of interactions in the interface of miRNAs and epigenetics. For example, epigenetic mechanisms can silence miRNA coding sites, and miRNAs can be the effectors of transcriptional gene silencing, targeting complementary promoters or silencing the expression of epigenetic modifier genes like MECP2 and EZH2 leading to global changes in the epigenome. Alterations in this regulatory machinery play a key role in the pathology of complex disorders including cancer and neurological diseases. For example, miRNA genes are frequently inactivated by epimutations in gliomas. Here we describe the interactions between epigenetic and ncRNA regulatory systems and discuss therapeutic potential, with an emphasis on tumors, cognitive disorders and neurodegenerative diseases.

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Section: Cross-regulation Of Mirnas and Epigenetic Mechanismsmentioning

confidence: 99%

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

2013

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“…Non-coding RNAs (ncRNAs) appear to play a critical role in regulating the transcriptional status of the genome, both in the nucleus and in the cytoplasm [Castel and Martienssen, 2013], and cannot be considered just as "transcriptional noise" [Mattick et al, 2009;Morris, 2009]. Three classes of short ncRNAs must be mentioned: short interfering RNAs (siRNAs), microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs).…”

Section: Rna Transcriptsmentioning

confidence: 99%

“…It is assumed that double-stranded RNAs are processed by the RNAi machinery into siRNAs that induce either degradation of complementary mRNAs (post-transcriptional gene silencing) or cause RNA-mediated DNA methylation (transcriptional gene silencing). Transcriptional gene silencing involves the recruitment of chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development [Mattick et al, 2009]. A similar regulatory role is played by miRNAs, short endogenous ncRNAs that adopt a hairpin conformation due to internal base complementarity, which regulate a large variety of biological functions [Wang et al, 2012].…”

Section: Rna Transcriptsmentioning

confidence: 99%

“…Four major layers of epigenetic controls have been identified: (1) cytosine methylation; (2) histone modifications; (3) chromatin remodeling; (4) RNA transcripts. Each of these transcriptional control levels is illustrated below, but it is important to appreciate that the last layer is probably the most critical since it targets the other chromatin modifying complexes to given loci in a sequence-specific manner [Mattick et al, 2009]. In a nutshell, dynamic changes to chromatin structure influence gene expression: genes are silenced when chromatin is condensed (heterochromatin), they are expressed when chromatin is "open" (euchromatin) and the appropriate transcription factors are available.…”

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confidence: 99%

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Epigenetics, fragile X syndrome and transcriptional therapy

Tabolacci

Chiurazzi

2013

American J of Med Genetics Pt A

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Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic mechanisms therefore include all transcriptional controls that determine how genes are expressed during development and differentiation, but also in individual cells responding to environmental stimuli. The purpose of this review is to examine the basic principles of epigenetic mechanisms and their contribution to human disorders with a particular focus on fragile X syndrome (FXS), the most common monogenic form of developmental cognitive impairment. FXS represents a prototype of the so-called repeat expansion disorders due to "dynamic" mutations, namely the expansion (known as "full mutation") of a CGG repeat in the 5 0 UTR of the FMR1 gene. This genetic anomaly is accompanied by epigenetic modifications (mainly DNA methylation and histone deacetylation), resulting in the inactivation of the FMR1 gene. The presence of an intact FMR1 coding sequence allowed pharmacological reactivation of gene transcription, particularly through the use of the DNA demethylating agent 5 0 -aza-2 0 -deoxycytydine and/or inhibitors of histone deacetylases. These treatments suggested that DNA methylation is dominant over histone acetylation in silencing the FMR1 gene. The importance of DNA methylation in repressing FMR1 transcription is confirmed by the existence of rare unaffected males carrying unmethylated full mutations. Finally, we address the potential use of epigenetic approaches to targeted treatment of other genetic conditions. Ó 2013 Wiley Periodicals, Inc.Key words: fragile X syndrome; epigenetics; transcriptional therapy INTRODUCTION When in 1942 Conrad H. Waddington coined the term "epigenetics," the exact nature of genes and their role in heredity and in transcriptional regulation was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype [Waddington, 1942]. The term is a portmanteau of the words epigenesis (differentiation of cells from their initial totipotent state in embryonic development) and genetics. Only in 2008 at a Cold Spring harbor meeting, consensus was reached on the definition of epigenetic trait, as "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" [Berger et al., 2009]. The greek prefix epi-refers to features that are "on top of" genetics, that is, all those stable but reversible changes to DNA, RNA and proteins that regulate gene expression and allow cells with the same DNA to do different things at different times.Broadly speaking, epigenetic mechanisms include all transcriptional controls that regulate gene expression, whether during development and differentiation or in mature cells responding to the environment. Epigenetic changes can be inherited (e.g., imprinting) and be relatively stable (e.g., chromosome X inactivation), but are often rapidly imposed or removed on a given locus according to cell needs. Four major layers of epigenetic controls have ...

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“…In addition to the structural function of the RNA within the cell cytoplasm, recent studies of the chromatin and chromosome structure, nuclear architecture, nuclear bodies, and the mechanisms of DNA replication indicate the presence of structural RNAs in the cell nucleus (Mattick et al 2009;Sasaki et al, 2009). Recently, RNA was found to play a structural role in the organization of chromatin from chicken liver and Drosophila S2 cell nuclei (Rodrıguez-Campos and Azorın, 2007).…”

Section: Structural Role Of Rna In Cell Nucleusmentioning

confidence: 99%

Teachings from the egg: New and unexpected functions of RNAs

Kloc

2009

Molecular Reproduction Devel

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SUMMARYLocalized mRNAs found in specific regions of somatic cells, germ cells, and embryos function through their protein translation products in cell polarization and development. Recent studies on Xenopus and Drosophila eggs and various somatic cells showed that some of the localized noncoding and coding RNAs play a structural (translation independent) role in maintaining the integrity of microtubule and microfilament cytoskeleton and/or may function in protein folding or as a scaffold for the assembly of cytoplasmic complexes essential for egg or embryo development. In addition, structural noncoding RNAs within the cell nucleus have been shown to be involved in the organization of chromatin, nuclear bodies, and DNA replication. The fact that some of the RNAs may have previously unforeseen structural functions, will change our view on traditional functions of RNAs and will open new frontiers in the field of RNA studies and therapeutic development.Mol. Reprod. Dev. 76: 922-932, 2009. ß

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RNA regulation of epigenetic processes

Cited by 331 publications

References 120 publications

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

Epigenetics, fragile X syndrome and transcriptional therapy

Teachings from the egg: New and unexpected functions of RNAs

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