Intergenic Transcripts Regulate the Epigenetic State of rRNA Genes

Mayer, Christine; Schmitz, Kerstin Maike; Li, Junwei; Grummt, Ingrid; Santoro, Raffaella

doi:10.1016/j.molcel.2006.03.028

Cited by 304 publications

(361 citation statements)

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“…Initially, it was inferred that enhancers alone are sufficient to explain the nucleolar dominance-like phenomenon in injected oocytes [78], though subsequent tests have revealed the need for a spacer promoter upstream of the enhancer repeats in order for X. laevis spacers to confer dominance in injected oocytes [81], suggesting a need for transcription of the spacer repeats in order to stimulate the downstream gene promoter. The mechanism by which spacer transcription might stimulate pre-rRNA transcription initiated from the adjacent gene promoter is unclear, particularly in light of recent data from the Grummt lab suggesting that spacer transcription participates in NoRC-dependent rRNA gene silencing [85].…”

Section: Are Nors Regulated As Single Loci or Is It Every Rrna Gene mentioning

confidence: 99%

rRNA gene silencing and nucleolar dominance: Insights into a chromosome-scale epigenetic on/off switch

Preuss

Pikaard

2007

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

135

105

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Ribosomal RNA (rRNA) gene transcription accounts for most of the RNA in prokaryotic and eukaryotic cells. In eukaryotes, there are hundreds (to thousands) of rRNA genes tandemly repeated head-to-tail within nucleolus organizer regions (NORs) that span millions of basepairs. These nucleolar rRNA genes are transcribed by RNA Polymerase I (Pol I) and their expression is regulated according to the physiological need for ribosomes. Regulation occurs at several levels, one of which is an epigenetic on/off switch that controls the number of active rRNA genes. Additional mechanisms then fine-tune transcription initiation and elongation rates to dictate the total amount of rRNA produced per gene. In this review, we focus on the DNA and histone modifications that comprise the epigenetic on/off switch. In both plants and animals, this system is important for controlling the dosage of active rRNA genes. The dosage control system is also responsible for the chromatinmediated silencing of one parental set of rRNA genes in genetic hybrids, a large-scale epigenetic phenomenon known as nucleolar dominance.Keywords epigenetic phenomena; RNA polymerase I; DNA methylation; cytosine methylation; histone methylation; histone deacetylation; histone deacetylase; transcription; ribosomal RNA; nucleolus; nucleolus organizer region Large scale cytological effects of rRNA gene regulation: nucleolus and secondary constriction formationThe most prominent feature of a eukaryotic nucleus during interphase is the nucleolus (Figure 1), a region that contains relatively little chromosomal DNA but is rich in RNAs, proteins and ribonucleoprotein particles, including the large and small ribosome subunits as they undergo assembly [1][2][3]. The location of a nucleolus is not determined randomly; instead its formation is determined by the position of a discrete chromosomal locus known as a nucleolus organizer region, or NOR [4]. This fact was discovered based on an intriguing property: upon condensation of chromosomes at metaphase, NORs fail to condense to the same extent as surrounding chromosomal sequences and thus give rise to "secondary constrictions", with "primary constrictions" being defined as the centromeres (see Figure 1). Heitz initially noted that nucleoli form at, or very near, the sites of secondary constrictions [5] and McClintock soon thereafter obtained direct evidence [6]. She identified a maize line in which a chromosome break at or near the secondary constriction on chromosome 9, followed by translocation of one *Author to whom correspondence should be addressed: pikaard@biology2.wustl.edu, phone: Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the conte...

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Section: Are Nors Regulated As Single Loci or Is It Every Rrna Gene mentioning

confidence: 99%

rRNA gene silencing and nucleolar dominance: Insights into a chromosome-scale epigenetic on/off switch

Preuss

Pikaard

2007

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

135

105

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“…Transcriptional silencing involves DNA methylation at a critical CpG residue (CpG-133) within the upstream control element (UCE) of the rDNA promoter, thereby impairing binding of the transcription factor UBF and abrogating transcription complex formation . Importantly, NoRC function requires the association of TIP5 with RNA that originates from an RNA polymerase I (Pol I) promoter located in the intergenic spacer ;2 kb upstream of the pre-rRNA transcription start site (Mayer et al 2006). These intergenic transcripts are of low abundance and usually do not accumulate in vivo because they are rapidly degraded or processed into 150-to 250-nucleotide (nt) RNAs that are shielded from degradation by binding to NoRC.…”

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confidence: 99%

Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes

Schmitz¹,

Mayer²,

Postepska³

et al. 2010

Genes Dev.

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445

400

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Noncoding RNAs are important components of regulatory networks controlling the epigenetic state of chromatin. We analyzed the role of pRNA (promoterassociated RNA), a noncoding RNA that is complementary to the rDNA promoter, in mediating de novo CpG methylation of rRNA genes (rDNA). We show that pRNA interacts with the target site of the transcription factor TTF-I, forming a DNA:RNA triplex that is specifically recognized by the DNA methyltransferase DNMT3b. The results reveal a compelling new mechanism of RNA-dependent DNA methylation, suggesting that recruitment of DNMT3b by DNA:RNA triplexes may be a common and generally used pathway in epigenetic regulation.Supplemental material is available at http://www.genesdev.org.Received April 28, 2010; revised version accepted August 26, 2010. Noncoding RNAs (ncRNAs) play a profound and complex role in regulating gene expression (Goodrich and Kugel 2009). While the mechanistic details of how RNA and chromatin are connected remain unclear, there is increasing evidence that epigenetic regulation likely represents a balanced interplay of both RNA and chromatin fields (Bernstein and Allis 2005;Mattick 2009). Previous studies have established that ncRNA plays a key role in epigenetic silencing of rRNA genes. Mammalian genomes contain several clusters of tandemly arrayed rRNA genes (rDNA), of which only a subset is transcribed. Silent rDNA repeats are marked by heterochromatic histone modifications and CpG methylation of the rDNA promoter . The establishment and maintenance of the heterochromatic state is mediated by NoRC (Strohner et al. 2001), a chromatin remodeling complex comprising the ATPase SNF2h and a large subunit, termed TIP5 (TTF-Iinteracting protein #5). NoRC silences rRNA genes by recruiting enzymes that mediate heterochromatin formation and silencing (Zhou et al. 2002;Zhou and Grummt 2005). Transcriptional silencing involves DNA methylation at a critical CpG residue (CpG-133) within the upstream control element (UCE) of the rDNA promoter, thereby impairing binding of the transcription factor UBF and abrogating transcription complex formation . Importantly, NoRC function requires the association of TIP5 with RNA that originates from an RNA polymerase I (Pol I) promoter located in the intergenic spacer ;2 kb upstream of the pre-rRNA transcription start site (Mayer et al. 2006). These intergenic transcripts are of low abundance and usually do not accumulate in vivo because they are rapidly degraded or processed into 150-to 250-nucleotide (nt) RNAs that are shielded from degradation by binding to NoRC. These NoRC-associated transcripts are termed pRNA (for promoter-associated RNA), as their sequence matches the rDNA promoter. TIP5 recognizes the secondary structure of pRNA, and the interaction of TIP5 with pRNA changes the structure of both pRNA and NoRC in an induced fit mechanism (Mayer et al. 2008). Antisensemediated depletion of pRNA leads to nucleoplasmic distribution of NoRC, hypomethylation of rDNA, and enhanced Pol I transcription. ''RNA refeeding'' a...

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“…The rDNA and nucleolus have played a prominent role in evolving theories of aging, metabolism, cell differentiation, cell cycle control, cancer progression, and gene regulation (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The rDNA is of particular interest in understanding heterochromatin because it is known to be regulated by epigenetic modification (20)(21)(22)(23)(24), is associated with both active and repressive protein modification (25,26), can affect variegation at unlinked genes (27,28), can itself induce variegation (29)(30)(31), and may change its size and regulation through the lifespan of an organism (32,33). Few studies, however, have probed the connection between the rDNA, nucleolus, and heterochromatin formation in the nucleus.…”

mentioning

confidence: 99%

Ribosomal DNA contributes to global chromatin regulation

Paredes

Maggert

2009

Proc. Natl. Acad. Sci. U.S.A.

139

144

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The 35S ribosomal RNA genes (rDNA) are organized as repeated arrays in many organisms. Epigenetic regulation of transcription of the rRNA results in only a subset of copies being transcribed, making rDNA an important model for understanding epigenetic chromatin modification. We have created an allelic series of deletions within the rDNA array of the Drosophila Y chromosome that affect nucleolus size and morphology, but do not limit steady-state rRNA concentrations. These rDNA deletions result in reduced heterochromatin-induced gene silencing elsewhere in the genome, and the extent of the rDNA deletion correlates with the loss of silencing. Consistent with this, chromosomes isolated from strains mutated in genes required for proper heterochromatin formation have very small rDNA arrays, reinforcing the connection between heterochromatin and the rDNA. In wild-type cells, which undergo spontaneous natural rDNA loss, we observed the same correlation between loss of rDNA and loss of heterochromatin-induced silencing, showing that the volatility of rDNA arrays may epigenetically influence gene expression through normal development and differentiation. We propose that the rDNA contributes to a balance between heterochromatin and euchromatin in the nucleus, and alterations in rDNA-induced or natural-affect this balance.Drosophila ͉ epigenetics ͉ heterochromatin ͉ nucleolus ͉ rDNA C hromatin within the nucleus is divided into cytologically heterochromatic and euchromatic compartments (1). This division reflects very different functional influences on gene expression (2). Many genes adopt more ''heterochromatin-like'' features when inactivated, including cytological appearance and association with specific proteins or post-translational modifications. This has led to hypotheses that similar mechanisms regulate facultatively inactivated genes or chromosomes, constitutively heterochromatic regions of the genome, and developmentally repressed genes (3). Understanding the interplay between heterochromatin and euchromatin, then, is fundamental in understanding the control of epigenetic regulation of the genome.Gene products involved in heterochromatin formation have been primarily identified by observing the effect of mutations on position effect variegation (PEV), which manifests as mosaic expression of a gene placed in a heterochromatic context. Many of these mutations act dominantly, thus the genes are thought to encode dosesensitive components of heterochromatin (4). Equally important to models of heterochromatin formation is the observation that the amount of constitutive heterochromatin in the nucleus affects heterochromatin-induced PEV at unlinked genes (5). In this model, gene products act as a ''source'' of heterochromatin forming potential, and DNA sequences destined to be heterochromatic as a ''sink.'' A balance is normally maintained between gene products and target DNA in the genome, although no proposed mechanism satisfactorily accounts for how this balance is maintained during division, determination, and differe...

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Intergenic Transcripts Regulate the Epigenetic State of rRNA Genes

Cited by 304 publications

References 33 publications

rRNA gene silencing and nucleolar dominance: Insights into a chromosome-scale epigenetic on/off switch

rRNA gene silencing and nucleolar dominance: Insights into a chromosome-scale epigenetic on/off switch

Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes

Ribosomal DNA contributes to global chromatin regulation

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