Noncoding RNAs: Regulators of the Mammalian Transcription Machinery

Eidem, Tess M.; Kugel, Jennifer F.; Goodrich, James A.

doi:10.1016/j.jmb.2016.02.019

Cited by 44 publications

(33 citation statements)

References 48 publications

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“…The fact that the basal methylation pattern is established through interactions between cis-acting and early-embryonic transacting factors (5) that determine the positioning of transcription complexes on the DNA may have far reaching implications. Thus, while the expression of these regulatory proteins and perhaps noncoding RNA factors (38) may be largely intrinsic to the embryonic state, one can speculate that this composition may also be influenced by local environmental effectors, both in the early embryo as well as in the gametes. If this were the case, these interactions could provide a sophisticated mechanism for events that occur in the gametes to ultimately influence the overall methylation pattern of the offspring (39).…”

Section: Discussionmentioning

confidence: 99%

Role of transcription complexes in the formation of the basal methylation pattern in early development

Greenfield

Tabib

Keshet

et al. 2018

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

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Following erasure in the blastocyst, the entire genome undergoes de novo methylation at the time of implantation, with CpG islands being protected from this process. This bimodal pattern is then preserved throughout development and the lifetime of the organism. Using mouse embryonic stem cells as a model system, we demonstrate that the binding of an RNA polymerase complex on DNA before de novo methylation is predictive of it being protected from this modification, and tethering experiments demonstrate that the presence of this complex is, in fact, sufficient to prevent methylation at these sites. This protection is most likely mediated by the recruitment of enzyme complexes that methylate histone H3K4 over a local region and, in this way, prevent access to the de novo methylation complex. The topological pattern of H3K4me3 that is formed while the DNA is as yet unmethylated provides a strikingly accurate template for modeling the genomewide basal methylation pattern of the organism. These results have far-reaching consequences for understanding the relationship between RNA transcription and DNA methylation. development | epigenetics | inheritance | histomodification I n animals, the genome-wide DNA methylation pattern is initially erased in the early embryo and then reestablished in each individual at about the time of implantation. This is carried out by a process in which almost all of the DNA is subject to de novo methylation while CpG island-like regions are protected on the basis of underlying sequence motifs (1), but the biological logic and molecular mechanism of this process are still unknown. Analysis of these CpG-rich sites indicates that they are highly enriched for transcription start sites and characterized by the presence of binding motifs for many transcription factors (2). This close correlation suggested the possibility that protection from de novo methylation may actually be dictated by the binding of transcription complexes at recognized sites in the preimplantation embryo. In this work, we have used bioinformatic tools as well as genetic techniques to test this idea. The results of these experiments lead to a concept for how DNA methylation functions during development. ResultsEmbryonic stem (ES) cells represent an excellent system for studying the process of global de novo methylation that takes place at the time of implantation. Although initially derived from the blastocyst stage of development, these cells harbor a DNA methylation pattern that is almost identical to the implantationstage embryo (∼E6.5) (3, 4). Furthermore, unlike somatic cells in culture, ES cells constantly maintain the ability to actively de novo methylate newly introduced DNA sequences while at the same time protecting CpG islands (5-7). Since we were interested in characterizing the factors that may play a role in the formation of this pattern, we needed a model of the genomic landscape as it existed before de novo methylation. To this end, we took advantage of ES cells carrying knockouts (TKO) for all three DNA methyl...

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Section: Discussionmentioning

confidence: 99%

Role of transcription complexes in the formation of the basal methylation pattern in early development

Greenfield

Tabib

Keshet

et al. 2018

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

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“…Most of them “work” only under certain (stress) conditions and are often tissue-specific [13, 17]. For example, NRSE RNA (neuron-restrictive silencer element) is expressed in stem cells and associated with the transcriptional repressor NRSF/REST responsible for neuron-specific gene silencing.…”

Section: Other Rnas Involved In the Regulation Of Transcription Factomentioning

confidence: 99%

“…This occurs primarily through various epigenetic mechanisms; in particular, chromatin remodeling (this area of ncRNA functioning has been studied much better than others) [12, 13]. The well-known examples of such ncRNAs include XIST RNA (X-inactive specific transcript), roX RNA, HOTAIR (Hox transcript antisense intergenic RNA); enhancer RNAs NRIP1, GREB1, KLK; and NEAT1 RNA (nuclear enriched abundant transcript 1), which is responsible for paraspeckle formation in tumor cell nuclei.…”

Section: Introductionmentioning

confidence: 99%

Non-coding RNAs As Transcriptional Regulators In Eukaryotes

Burenina¹,

Oretskaya²,

Kubareva³

2017

Acta Naturae

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Non-coding RNAs up to 1,000 nucleotides in length are widespread in eukaryotes and fulfil various regulatory functions, in particular during chromatin remodeling and cell proliferation. These RNAs are not translated into proteins: thus, they are non-coding RNAs (ncRNAs). The present review describes the eukaryotic ncRNAs involved in transcription regulation, first and foremost, targeting RNA polymerase II (RNAP II) and/or its major proteinaceous transcription factors. The current state of knowledge concerning the regulatory functions of SRA and TAR RNA, 7SK and U1 snRNA, GAS5 and DHFR RNA is summarized herein. Special attention is given to murine B1 and B2 RNAs and human Alu RNA, due to their ability to bind the active site of RNAP II. Discovery of bacterial analogs of the eukaryotic small ncRNAs involved in transcription regulation, such as 6S RNAs, suggests that they possess a common evolutionary origin.

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“…Dozens of ncRNAs modulating the activity of transcription factors are currently known. Most of them "work" only under certain (stress) conditions and are often tissue-specific [13,17]. For example, NRSE RNA (neuron-restrictive silencer element) is expressed in stem cells and associated with the transcriptional repressor NRSF/REST responsible for neuron-specific gene silencing.…”

Section: Other Rnas Involved In the Regulation Of Transcription Factomentioning

confidence: 99%