RNA-mediated epigenetic regulation of DNA copy number

Nowacki, Mariusz; Haye, Joanna E.; Fang, Wenwen; Vijayan, Vikram; Landweber, Laura F.

doi:10.1073/pnas.1012236107

Cited by 67 publications

(67 citation statements)

References 41 publications

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“…The long macronuclear RNAs in Oxytricha have an additional surprising function in epigenetic genome regulation: These RNAs regulate not only the genome rearrangements, but also the chromosome copy numbers in the macronuclear development (Nowacki et al 2010). In the macronucleus, chromosomes of the diploid zygotic nucleus are amplified by endoreplication.…”

Section: Dna Unscrambling Is Templated By Maternal Rnasmentioning

confidence: 99%

Epigenetics of Ciliates

Chalker

Meyer

Mochizuki

2013

Cold Spring Harbor Perspectives in Biology

103

114

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SUMMARYResearch using ciliates revealed early examples of epigenetic phenomena and continues to provide novel findings. These protozoans maintain separate germline and somatic nuclei that carry transcriptionally silent and active genomes, respectively. Examining the differences in chromatin within distinct nuclei of Tetrahymena identified histone variants and established that transcriptional regulators act by modifying histones. Formation of somatic nuclei requires both transcriptional activation of silent chromatin and large-scale DNA elimination. This somatic genome remodeling is directed by homologous RNAs, acting with an RNA interference (RNAi)-related machinery. Furthermore, the content of the parental somatic genome provides a homologous template to guide this genome restructuring. The mechanisms regulating ciliate DNA rearrangements reveal the surprising power of homologous RNAs to remodel the genome and transmit information transgenerationally.Outline

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Section: Dna Unscrambling Is Templated By Maternal Rnasmentioning

confidence: 99%

Epigenetics of Ciliates

Chalker

Meyer

Mochizuki

2013

Cold Spring Harbor Perspectives in Biology

103

114

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“…On the basis of sequence, the telomere-to-telomere RNA transcripts of MAC chromosomes may perform myriad roles during post-zygotic development. For example, the lncRNAs not only guide DNA rearrangement, but also establish DNA dosage levels (Nowacki et al 2010) and provide the possible precursors to piRNAs that protect regions of the germline DNA from elimination (Fang et al 2012;Zahler et al 2012). The present study identified template RNAs for both scrambled and nonscrambled loci, as well as for "IES-less" chromosomes that require no DNA deletion and only excision from the MIC genome plus telomere addition.…”

Section: Discussionmentioning

confidence: 99%

Thousands of RNA-cached copies of whole chromosomes are present in the ciliate Oxytricha during development

Lindblad

Bracht

Williams

et al. 2017

RNA

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The ciliate Oxytricha trifallax maintains two genomes: a germline genome that is active only during sexual conjugation and a transcriptionally active, somatic genome that derives from the germline via extensive sequence reduction and rearrangement. Previously, we found that long noncoding (lnc) RNA "templates"-telomere-containing, RNA-cached copies of mature chromosomes-provide the information to program the rearrangement process. Here we used a modified RNA-seq approach to conduct the first genome-wide search for endogenous, telomere-to-telomere RNA transcripts. We find that during development, Oxytricha produces long noncoding RNA copies for over 10,000 of its 16,000 somatic chromosomes, consistent with a model in which Oxytricha transmits an RNA-cached copy of its somatic genome to the sexual progeny. Both the primary sequence and expression profile of a somatic chromosome influence the temporal distribution and abundance of individual template RNAs. This suggests that Oxytricha may undergo multiple rounds of DNA rearrangement during development. These observations implicate a complex set of thousands of long RNA molecules in the wiring and maintenance of a highly elaborate somatic genome architecture.

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“…During the sexual phase of the life cycle, genome-wide transcription of the somatic chromosomes from the parental macronucleus produces long noncoding template RNAs that guide DNA rearrangements (Nowacki et al 2008;Khurana et al 2014;Lindblad et al 2017) and also regulate chromosome copy number in the progeny (Nowacki et al 2010); however, the mechanism is unclear. The new class of sRNAs reported in this manuscript could derive from these Small RNAs and DNA copy-number regulation www.rnajournal.org 25 maternal template RNAs that appear post fertilization.…”

Section: Discussionmentioning

confidence: 99%

“…Either the cells with the strongest phenotype are depleted from the asexually growing population, consistent with the increased death rate among the mutants, or alternatively, the paralogs of genes under study may act redundantly in the DNA dosage pathway, thus ameliorating the effects we report here. On the other hand, the conjugation-specific lncRNAs (Nowacki et al 2010) are potential substrates for these sRNAs, and their amplification could lead to a stronger downstream effect on the target DNA copy number.…”

Section: Discussionmentioning

confidence: 99%

“…S3F). These observations suggest that, rather than deriving from mRNA precursors, these sRNAs, like Oxytricha piRNAs (Fang et al 2012), could be processed from long, noncoding RNAs, possibly from the same RNA molecules that establish chromosome copy number post-conjugation (Nowacki et al 2010).…”

Section: Dcl-1 and Rdrp-dependent Small Rnas In Asexually Growing Oxymentioning

confidence: 99%

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Small RNA-mediated regulation of DNA dosage in the ciliate Oxytricha

Khurana

Clay

Moreira

et al. 2017

RNA

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Dicer-dependent small noncoding RNAs play important roles in gene regulation in a wide variety of organisms. Endogenous small interfering RNAs (siRNAs) are part of an ancient pathway of transposon control in plants and animals. The ciliate, Oxytricha trifallax, has approximately 16,000 gene-sized chromosomes in its somatic nucleus. Long noncoding RNAs establish high ploidy levels at the onset of sexual development, but the factors that regulate chromosome copy numbers during cell division and growth have been a mystery. We report a novel function of a class of Dicer (Dcl-1)-and RNA-dependent RNA polymerase (RdRP)-dependent endogenous small RNAs in regulating chromosome copy number and gene dosage in O. trifallax. Asexually growing populations express an abundant class of 21-nt sRNAs that map to both coding and noncoding regions of most chromosomes. These sRNAs are bound to chromatin and their levels surprisingly do not correlate with mRNA levels. Instead, the levels of these small RNAs correlate with genomic DNA copy number. Reduced sRNA levels in dcl-1 or rdrp mutants lead to concomitant reduction in chromosome copy number. Furthermore, these cells show no signs of transposon activation, but instead display irregular nuclear architecture and signs of replication stress. In conclusion, Oxytricha Dcl-1 and RdRPdependent small RNAs that derive from the somatic nucleus contribute to the maintenance of gene dosage, possibly via a role in DNA replication, offering a novel role for these small RNAs in eukaryotes.

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RNA-mediated epigenetic regulation of DNA copy number

Cited by 67 publications

References 41 publications

Epigenetics of Ciliates

Epigenetics of Ciliates

Thousands of RNA-cached copies of whole chromosomes are present in the ciliate Oxytricha during development

Small RNA-mediated regulation of DNA dosage in the ciliate Oxytricha

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