Identification of YTH Domain-Containing Proteins as the Readers for N 1-Methyladenosine in RNA

Wang

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

et al. 2018

136

107

IFN–stimulated genes (ISGs) are essential effectors of the IFN-dependent antiviral immune response. Dysregulation of ISG expression can cause dysfunctional antiviral responses and autoimmune disorders. Epitranscriptomic regulation, such as N6-methyladenosine (m6A) modification of mRNAs, plays key roles in diverse biological processes. Here, we found that the m6A “reader” YT521-B homology domain-containing family 3 (YTHDF3) suppresses ISG expression under basal conditions by promoting translation of the transcription corepressor forkhead box protein O3 (FOXO3). YTHDF3 cooperates with two cofactors, PABP1 and eIF4G2, to promote FOXO3 translation by binding to the translation initiation region of FOXO3 mRNA. Both the YTH and the P/Q/N-rich domains of YTHDF3 were required for FOXO3 RNA-binding capacity, however, METTL3-mediated m6A modification was not involved in the process observed. Moreover, YTHDF3−/− mice had increased ISG levels and were resistant to several viral infections. Our findings uncover the role of YTHDF3 as a negative regulator of antiviral immunity through the translational promotion of FOXO3 mRNA under homeostatic conditions, adding insight into the networks of RNA-binding protein-RNA interactions in homeostatically maintaining host antiviral immune function and preventing inflammatory response.

Section: Foxo3 Is Pivotal In Ythdf3-mediated Negative Regulation Of Asupporting

confidence: 65%

Section: Foxo3 Is Pivotal In Ythdf3-mediated Negative Regulation Of Amentioning

confidence: 99%

RNA-binding protein YTHDF3 suppresses interferon-dependent antiviral responses by promoting FOXO3 translation

Wang

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

et al. 2018

136

107

“…Immunoprecipitation, pull‐down, mass‐spectrometry, and RNA‐seq approaches have begun to identify proteins whose interactions with mRNAs are mediated by modifications. These studies reveal that m 6 A, m 1 A, and m 5 C are specifically recognized by proteins that can either read or erase modifications to alter mRNA translation, localization, and stabilization (reviewed in X. Dai et al, ; X. Li et al, ; F. Liu et al, ; Peer et al, ; Roundtree, Evans, et al, ; S. Schwartz, ; Trixl & Lusser, ; Yang et al, ). To date, no “readers” or “erasers” of other mRNA modifications have been reported, though it has been proposed that the ribosome can serve as a universal reader of modifications in mRNA coding regions (Gilbert, Bell, & Schaening, 2016).…”

Section: Current Quantitative Perspective On Mrna Modificationsmentioning

confidence: 99%

A molecular‐level perspective on the frequency, distribution, and consequences of messenger RNA modifications

2020

Cells use chemical modifications to alter the sterics, charge, and conformations of large biomolecules, modulating their biogenesis, function, and stability. Until recently post‐transcriptional RNA modifications were thought to be largely limited to nonprotein coding RNA species. However, this dogma has rapidly transformed with the discovery of a host of modifications in protein coding messenger RNAs (mRNAs). Recent advancements in genome‐wide sequencing technologies have enabled the identification of mRNA modifications as a potential new frontier in gene regulation—leading to the development of the epitranscriptome field. As a result, there has been a flurry of multiple groundbreaking discoveries, including new modifications, nucleoside modifying enzymes (“writers” and “erasers”), and RNA binding proteins that recognize chemical modifications (“readers”). These discoveries opened the door to understanding how post‐transcriptional mRNA modifications can modulate the mRNA lifecycle, and established a link between the epitranscriptome and human health and disease. Despite a rapidly growing recognition of their importance, fundamental questions regarding the identity, prevalence, and functional consequences of mRNA modifications remain to be answered. Here, we highlight quantitative studies that characterize mRNA modification abundance, frequency, and interactions with cellular machinery. As the field progresses, we see a need for the further integration of quantitative and reductionist approaches to complement transcriptome wide studies in order to establish a molecular‐level framework for understanding the consequences of mRNA chemical modifications on biological processes. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry RNA Processing > RNA Editing and Modification

“…Similar to m6A, installing a methyl group at the N1 position of adenosine forms N1-methyladenosine (m1A). Nine members of m1A regulators have been identified till now including writers (TRMT6, TRMT61A, TRMT10C), readers (YTHDF1, YTHDC1) and erasers (ALKBH1, ALKBH3) [5,92,93]. Dysregulation of m1A components was found to promote the progression of gastric cancer and bladder cancer via activation of several oncogenic pathways such as PI3K/AKT/mTOR and ErbB Pathways [94].…”

Section: N1-methyladenosine (M1a) 5-methylcytidine (M5c) and Pseudoumentioning

confidence: 99%

Epigenetic modulations of noncoding RNA: a novel dimension of Cancer biology

Yang

Liu

et al. 2020

Mol Cancer

Empowered by recent advances of sequencing techniques, transcriptome-wide studies have characterized over 150 different types of post-transcriptional chemical modifications of RNA, ranging from methylations of single base to complex installing reactions catalyzed by coordinated actions of multiple modification enzymes. These modifications have been shown to regulate the function and fate of RNAs and further affecting various cellular events. However, the current understanding of their biological functions in human diseases, especially in cancers, is still limited. Once regarded as "junk" or "noise" of the transcriptome, noncoding RNA (ncRNA) has been proved to be involved in a plethora of cellular signaling pathways especially those regulating cancer initiation and progression. Accumulating evidence has demonstrated that ncRNAs manipulate multiple phenotypes of cancer cells including proliferation, metastasis and chemoresistance and may become promising biomarkers and targets for diagnosis and treatment of cancer. Importantly, recent studies have mapped plenty of modified residues in ncRNA transcripts, indicating the existence of epigenetic modulation of ncRNAs and the potential effects of RNA modulation on cancer progression. In this review, we briefly introduced the characteristics of several main epigenetic marks on ncRNAs and summarized their consecutive effects on cancer cells. We found that ncRNAs could act both as regulators and targets of epigenetic enzymes, which indicated a cross-regulating network in cancer cells and unveil a novel dimension of cancer biology. Moreover, by epitomizing the knowledge of RNA epigenetics, our work may pave the way for the design of patienttailored therapeutics of cancers.