Following its transcription, RNA can be modified by >170 chemically distinct types of modifications - the epitranscriptome. In recent years, there have been substantial efforts to uncover and characterize the modifications present on mRNA, motivated by the potential of such modifications to regulate mRNA fate and by discoveries and advances in our understanding of N 6-methyladenosine (m6A). Here, we review our knowledge regarding the detection, distribution, abundance, biogenesis, functions and possible mechanisms of action of six of these modifications - pseudouridine (Ψ), 5-methylcytidine (m5C), N 1-methyladenosine (m1A), N 4-acetylcytidine (ac4C), ribose methylations (Nm) and N 7-methylguanosine (m7G). We discuss the technical and analytical aspects that have led to inconsistent conclusions and controversies regarding the abundance and distribution of some of these modifications. We further highlight shared commonalities and important ways in which these modifications differ with respect to m6A, based on which we speculate on their origin and their ability to acquire functions over evolutionary timescales.

The epitranscriptome beyond m6A.

N6-methyladenosine (m6A) modification plays important roles in various cellular responses by regulating mRNA biology. However, how m6A modification is involved in innate immunity via affecting the translation of immune transcripts remains to be further investigated. Here we report that RNA methyltransferase Mettl3-mediated mRNA m6A methylation promotes dendritic cell (DC) activation and function. Specific depletion of Mettl3 in DC resulted in impaired phenotypic and functional maturation of DC, with decreased expression of co-stimulatory molecules CD40, CD80 and cytokine IL-12, and reduced ability to stimulate T cell responses both in vitro and in vivo. Mechanistically, Mettl3-mediated m6A of CD40, CD80 and TLR4 signaling adaptor Tirap transcripts enhanced their translation in DC for stimulating T cell activation, and strengthening TLR4/NF-κB signaling-induced cytokine production. Our findings identify a new role for Mettl3-mediated m6A modification in increasing translation of certain immune transcripts for physiological promotion of DC activation and DC-based T cell response.

/pdf/mettl3-mediated-mrna-m-6-a-methylation-promotes-dendritic-wb6gqhnjke.pdf

Mettl3-mediated mRNA m 6 A methylation promotes dendritic cell activation.

Transcriptome-wide Mapping of Internal N7-Methylguanosine Methylome in Mammalian mRNA.

RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N6-methyladenosine (m6A), 5-methylcytosine (m5C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.

/pdf/the-role-of-m6a-m5c-and-ps-rna-modifications-in-cancer-novel-3hpq6nyhan.pdf

The role of m6A, m5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities.

Innate immune cells have complex signalling pathways for sensing pathogens and initiating innate immune responses against infection. These pathways are tightly regulated at different levels, including by epigenetic regulators. In this Review, we discuss studies revealing the epigenetic mechanisms, as well as the post-transcriptional and post-translational modifications by chromatin modifiers, that underlie the establishment of these signalling networks and the rapid induction of innate immune molecules during infection. We also discuss how pathogens use their own products, as well as host components, to target host epigenomes for immune evasion and survival. We describe the crosstalk between epigenetic regulators and new modulators, such as inflammation-specific metabolites, and how we might deconstruct dynamic chromatin patterns and identify critical chromatin modifiers of host–pathogen interactions. This Review describes the diverse and dynamic chromatin modifications that ensure rapid and appropriate innate immune responses to infection. It also discusses how pathogens themselves modify host responses through epigenetic mechanisms to evade elimination.

Epigenetic regulation of the innate immune response to infection.

Varieties of RNA modification form the epitranscriptome for post-transcriptional regulation. 5-Methylcytosine (5-mC) is a sparse RNA modification in messenger RNA (mRNA) under physiological conditions. The function of RNA 5-hydroxymethylcytosine (5-hmC) oxidized by ten-eleven translocation (Tet) proteins in Drosophila has been revealed more recently. However, the turnover and function of 5-mC in mammalian mRNA have been largely unknown. Tet2 suppresses myeloid malignancies mostly in an enzymatic activity-dependent manner, and is important in resolving inflammatory response in an enzymatic activity-independent way. Myelopoiesis is a common host immune response in acute and chronic infections; however, its epigenetic mechanism needs to be identified. Here we demonstrate that Tet2 promotes infection-induced myelopoiesis in an mRNA oxidation-dependent manner through Adar1-mediated repression of Socs3 expression at the post-transcription level. Tet2 promotes both abdominal sepsis-induced emergency myelopoiesis and parasite-induced mast cell expansion through decreasing mRNA levels of Socs3, a key negative regulator of the JAK-STAT pathway that is critical for cytokine-induced myelopoiesis. Tet2 represses Socs3 expression through Adar1, which binds and destabilizes Socs3 mRNA in a RNA editing-independent manner. For the underlying mechanism of Tet2 regulation at the mRNA level, Tet2 mediates oxidation of 5-mC in mRNA. Tet2 deficiency leads to the transcriptome-wide appearance of methylated cytosines, including ones in the 3' untranslated region of Socs3, which influences double-stranded RNA formation for Adar1 binding, probably through cytosine methylation-specific readers, such as RNA helicases. Our study reveals a previously unknown regulatory role of Tet2 at the epitranscriptomic level, promoting myelopoiesis during infection in the mammalian system by decreasing 5-mCs in mRNAs. Moreover, the inhibitory function of cytosine methylation on double-stranded RNA formation and Adar1 binding in mRNA reveals its new physiological role in the mammalian system.

Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation

Demethylase Kdm6a epigenetically promotes IL-6 and IFN-β production in macrophages.

Background Small RNAs (sRNAs) extensively mediate gene-specific chromatin regulation in lower organisms. As a dominant type of functional sRNAs in mature mammals, microRNAs mainly regulate gene expression at post-transcription level in the cytoplasm. Currently, whether there exists a type of nuclear-localized sRNAs mediating gene-specific epigenetic regulation in mature mammalian cells remains largely unclear. Here, we profiled sRNAs enriched in the nucleus and investigated their function in mediating gene-specific epigenetic regulation in anti-tumor immunity. Methods We established cytoplasmic and nuclear transcriptomes of sRNAs of dendritic cells (DCs) using high-throughput sequencing. Transcription abundances of sRNAs and mRNAs were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay. The associations between sRNAs and Argonaute (AGO) proteins were detected by RNA immunoprecipitation analysis. Synthesized sRNAs and locked nucleic acid (LNA) -modified sRNA inhibitors were used to screen the function of sRNAs in innate immune cells. The effect of sRNA on the enrichment of either chromatin remodeler or histone modification at the gene promoter was analyzed by chromatin immunoprecipitation (ChIP)-qPCR assay. Chromatin accessibility qPCR assay was used to detect the accessibility of gene promoters. A B16 melanoma-bearing mouse model was established to determine the function of sRNAs in tumor-associated macrophages (TAMs) and their effect on tumor growth. Results We identified a new class of nucleus-localized sRNAs, named snRNA/snoRNA-derived nuclear RNAs (sdnRNAs). Some sdnRNAs were Dicer-independent and had no association with Argonaute proteins. sdnRNA-3, the most abundant Dicer-independent sdnRNAs identified in our analysis, was selected as a representative to examine the biological function of sdnRNAs. sdnRNA-3 selectively inhibited the transcription of Nos2 in macrophages during innate immune response by repressing the chromatin accessibility at Nos2 gene promoter. sdnRNA-3 promoted the enrichments of repressive chromatin-remodeling regulator Mi-2β and the repressive histone modification H3K27me3 at Nos2 gene promoter. In the B16 melanoma mouse model, we found higher expression of sdnRNA-3 in M2 TAMs than M1 TAMs and DCs. Transfer of sdnRNA-3-silenced macrophages inhibited tumor growth with increased expression of inducible nitric oxide synthase (iNOS) in TAMs. Conclusions Our results demonstrated that the sdnRNA-3 repressed the transcription of Nos2 by repressing chromatin accessibility at the promoter, providing new insights into the regulation of macrophage function in tumor immunity.

/pdf/dicer-independent-snrna-snorna-derived-nuclear-rna-3-3cr7jy7adi.pdf

Dicer-independent snRNA/snoRNA-derived nuclear RNA 3 regulates tumor-associated macrophage function by epigenetically repressing inducible nitric oxide synthase transcription.

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Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation

Demethylase Kdm6a epigenetically promotes IL-6 and IFN-β production in macrophages.

Dicer-independent snRNA/snoRNA-derived nuclear RNA 3 regulates tumor-associated macrophage function by epigenetically repressing inducible nitric oxide synthase transcription.