Evolving insights into RNA modifications and their functional diversity in the brain

Nainar, Sarah; Marshall, Paul R.; Tyler, Christina R.; Spitale, Robert C.; Bredy, Timothy W.

doi:10.1038/nn.4378

Cited by 68 publications

(67 citation statements)

References 85 publications

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“…A large variety of studies have shown that the activity ADARs (adenosine deaminases acting on RNAs), responsible for A-to-I editing, are highly expressed in nervous systems (Picardi et al 2015), and markedly increased during primate evolution (Paz-Yaacov et al 2010). These modifications do not only affect protein-coding genes, but also noncoding transcripts, and thus may be central to learning and plasticity in brain function (Lence et al 2016;Nainar et al 2016).…”

Section: Discussionmentioning

confidence: 99%

The RNA modification landscape in human disease

Jonkhout

Tran

Smith

et al. 2017

RNA

490

420

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RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.

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Section: Discussionmentioning

confidence: 99%

The RNA modification landscape in human disease

Jonkhout

Tran

Smith

et al. 2017

RNA

490

420

View full text Add to dashboard Cite

show abstract

“…Importantly, our findings are not only applicable to RNA structure, but also to the field of RNA modifications. RNA modifications are known to alter the structure, function and activity of RNA molecules [42][43][44][45][46][47][48] . Recent papers have analyzed multiple RNA-Seq datasets looking for mismatched nucleotide signatures, finding that many RNA sequences contain modified nucleosides, 29,30,49 , and in the last year, genome-wide maps identifying thousands of m 1 A modifications have been made available 50 .…”

Section: Discussionmentioning

confidence: 99%

Best practices for genome-wide RNA structure analysis: combination of mutational profiles and drop-off information

Novoa

Beaudoin

Giráldez

et al. 2017

Preprint

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Genome-wide RNA structure maps have recently become available through the coupling of in vivo chemical probing reagents with next-generation sequencing. Initial analyses relied on the identification of truncated reverse transcription reads to identify the chemically modified nucleotides, but recent studies have shown that mutational signatures can also be used.While these two methods have been employed interchangeably, here we show that they actually provide complementary information. Consequently, analyses using exclusively one of the two methodologies may disregard a significant portion of the structural information. We find that the identity and sequence environment of the modified nucleotide greatly affects the odds of introducing a mismatch or causing reverse transcriptase drop-off. Finally, we identify specific mismatch signatures generated by dimethyl sulfate probing that can be used to remove false positives typically produced in RNA structurome analyses, and how these signatures vary depending on the reverse transcription enzyme used.

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“…S1A-C.). However, the level of mRNA expression does not necessarily reflect the functional relevance of a given gene (25). Given previous findings of a role for Gadd45β in regulating contextual fear memory, we therefore designed shRNAs against all three members of the Gadd45 family according to established protocols (26), and validated these in vitro (SI Appendix Fig.…”

Section: Resultsmentioning

confidence: 99%

The DNA repair associated protein Gadd45γ regulates the temporal coding of immediate early gene expression and is required for the consolidation of associative fear memory

Leighton

et al. 2018

Preprint

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We would also like to thank Ms. Rowan Tweedale for helpful editing of the manuscript.Significance statement: How does the pattern of immediate early gene (IEG) transcription in the brain relate to the storage and accession of information, and what controls these patterns? This paper explores how GADD45g , a gene that is known to be involved with DNA modification and repair, regulates the temporal coding of IEGs underlying associative learning and memory. We reveal that, during fear learning, GADD45g serves to act as a coordinator of IEG expression and subsequent memory consolidation by directing temporally specific changes in active DNA demethylation at the promoter of plasticity-related IEGs.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/265355 doi: bioRxiv preprint first posted online Feb. 14, 2018; PNAS Gadd45 g and memory Visual abstract AbstractWe have identified a member of the Growth arrest and DNA damage (Gadd45) family, Gadd45g , which is known to be involved in the regulation of DNA repair, as a key player in the formation of associative fear memory. Gadd45g regulates the temporal dynamics of learning-induced immediate early gene (IEG) expression in the prelimbic prefrontal cortex through its interaction with DNA double-strand break (DSB)-mediated changes in DNA methylation. Our findings suggest a two-hit model of experience-dependent IEG activity and learning that comprises 1) a first wave of IEG expression governed by DSBs followed by an increase in DNA methylation, and 2) a second wave of IEG expression associated with Gadd45g and active DNA demethylation at the same site, which is necessary for memory consolidation.

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Evolving insights into RNA modifications and their functional diversity in the brain

Cited by 68 publications

References 85 publications

The RNA modification landscape in human disease

The RNA modification landscape in human disease

Best practices for genome-wide RNA structure analysis: combination of mutational profiles and drop-off information

The DNA repair associated protein Gadd45γ regulates the temporal coding of immediate early gene expression and is required for the consolidation of associative fear memory

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