SINE transcription by RNA polymerase III is suppressed by histone methylation but not by DNA methylation

Varshney, Dhaval; Vavrova-Anderson, Jana; Oler, Andrew J.; Cowling, Victoria H.; Cairns, Bradley R.; White, Robert J.

doi:10.1038/ncomms7569

Cited by 96 publications

(99 citation statements)

References 61 publications

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“…Alu expression contribution to genome regulation involves multiple mechanisms, and different approaches have been used to study it, including the analysis of RNA polymerase III activity, retrotransposition, noncoding RNAs, Alu mediated adenosine to inosine (A-to-I) RNA editing, and exonization among others (Oler et al 2012;Daniel et al 2015;Tajnik et al 2015;Varshney et al 2015;Klawitter et al 2016;Lin et al 2016;Moráles-Hernandez et al 2016;Nishikura 2016). Therefore, unveiling the specific contribution of each element to genome regulation requires targeted customized studies.…”

Section: Epigenetic and Functional Features Of Transcribed Alu Repeatsmentioning

confidence: 99%

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

et al. 2016

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Cancer cells exhibit multiple epigenetic changes with prominent local DNA hypermethylation and widespread hypomethylation affecting large chromosomal domains. Epigenome studies often disregard the study of repeat elements owing to technical complexity and their undefined role in genome regulation. We have developed NSUMA (Next-generation Sequencing of UnMethylated Alu), a cost-effective approach allowing the unambiguous interrogation of DNA methylation in more than 130,000 individual Alu elements, the most abundant retrotransposon in the human genome. DNA methylation profiles of Alu repeats have been analyzed in colon cancers and normal tissues using NSUMA and whole-genome bisulfite sequencing. Normal cells show a low proportion of unmethylated Alu (1%-4%) that may increase up to 10-fold in cancer cells. In normal cells, unmethylated Alu elements tend to locate in the vicinity of functionally rich regions and display epigenetic features consistent with a direct impact on genome regulation. In cancer cells, Alu repeats are more resistant to hypomethylation than other retroelements. Genome segmentation based on high/low rates of Alu hypomethylation allows the identification of genomic compartments with differential genetic, epigenetic, and transcriptomic features. Alu hypomethylated regions show low transcriptional activity, late DNA replication, and its extent is associated with higher chromosomal instability. Our analysis demonstrates that Alu retroelements contribute to define the epigenetic landscape of normal and cancer cells and provides a unique resource on the epigenetic dynamics of a principal, but largely unexplored, component of the primate genome.

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Section: Epigenetic and Functional Features Of Transcribed Alu Repeatsmentioning

confidence: 99%

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

et al. 2016

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“…11 Genome-wide analyses suggest that only »0.1% of Alu loci are transcribed or occupied by pol III in the cell lines investigated. [12][13][14] Other studies reported even lower pol III occupancy, [15][16][17] …”

Section: Sine Expression Can Have Detrimental Consequences and Is Submentioning

confidence: 99%

Selective repression of SINE transcription by RNA polymerase III

Varshney

Vavrova-Anderson

Oler

et al. 2015

Mobile Genetic Elements

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A million copies of the Alu short interspersed nuclear element (SINE) are scattered throughout the human genome, providing »11% of our total DNA. SINEs spread by retrotransposition, using a transcript generated by RNA polymerase (pol) III from an internal promoter. Levels of these pol IIIdependent Alu transcripts are far lower than might be expected from the abundance of the template. This was believed to reflect transcriptional suppression through DNA methylation, denying pol III access to most SINEs through chromatin-mediated effects. Contrary to expectations, our recent study found no evidence that methylation of SINE DNA reduces its occupancy or expression by pol III. However, histone H3 associated with SINEs is prominently methylated on lysine 9, a mark that correlates with transcriptional silencing. The SUV39 methyltransferases that deposit this mark can be found at many SINEs. Furthermore, a selective inhibitor of SUV39 stimulates pol III recruitment to these loci, as well as SINE expression. These data suggest that methylation of histone H3 rather than DNA may mediate repression of SINE transcription by pol III, at least under the conditions we studied.

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“…Only 24 Alus were bound to Pol III in more than one cell line [33], supporting the hypothesis that Alu elements are controlled by genetic or epigenetic features limiting their expression to a certain state or tissue. As suggested by a recent work combining epigenetic studies with ChIP-bisulphite-sequencing (ChIP-BSSeq) to map the methylation state of Pol III-bound Alus, it is the methylation of H3K9, rather than DNA, that suppresses accessibility of SINEs to the transcriptional machinery [35]. Among the novel Pol III loci, most interesting was the identification in human cells [24] and mouse liver [26] of a conserved antisense MIR (Mammalian Interspersed Repeat) located in the first intron of the POLR3E gene, which encodes the RPC5 subunit of Pol III.…”

Section: Chip-seq Reveals Pol III Binding Dynamics In Multiple Eukarymentioning

confidence: 99%

tRNA biology in the omics era: Stress signalling dynamics and cancer progression

Orioli

2016

BioEssays

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Recent years have seen a burst in the number of studies investigating tRNA biology. With the transition from a gene‐centred to a genome‐centred perspective, tRNAs and other RNA polymerase III transcripts surfaced as active regulators of normal cell physiology and disease. Novel strategies removing some of the hurdles that prevent quantitative tRNA profiling revealed that the differential exploitation of the tRNA pool critically affects the ability of the cell to balance protein homeostasis during normal and stress conditions. Furthermore, growing evidence indicates that the adaptation of tRNA synthesis to cellular dynamics can influence translation and mRNA stability to drive carcinogenesis and other pathological disorders. This review explores the contribution given by genomics, transcriptomics and epitranscriptomics to the discovery of emerging tRNA functions, and gives insights into some of the technical challenges that still limit our understanding of the RNA polymerase III transcriptional machinery.

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SINE transcription by RNA polymerase III is suppressed by histone methylation but not by DNA methylation

Cited by 96 publications

References 61 publications

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

Selective repression of SINE transcription by RNA polymerase III

tRNA biology in the omics era: Stress signalling dynamics and cancer progression

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