5-methylcytosine is often associated as an epigenetic modifier in DNA. However, it is also found increasingly in a plethora of RNA species, predominantly transfer RNAs, but increasingly found in cytoplasmic and mitochondrial ribosomal RNAs, enhancer RNAs, and a number of long noncoding RNAs. Moreover, this modification can also be found in messenger RNAs and has led to an increasing appreciation that RNA methylation can functionally regulate gene expression and cellular activities. In mammalian cells, the addition of m5C to RNA cytosines is carried out by enzymes of the NOL1/NOP2/SUN domain (NSUN) family as well as the DNA methyltransferase homologue DNMT2. In this regard, NSUN2 is a critical RNA methyltransferase for adding m5C to mRNA. In this review, using non-small cell lung cancer and other cancers as primary examples, we discuss the recent developments in the known functions of this RNA methyltransferase and its potential critical role in cancer.

https://www.mdpi.com/2073-4409/9/8/1758/pdf

The RNA Methyltransferase NSUN2 and Its Potential Roles in Cancer.

N6-methyladenosine and Neurological Diseases

Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity

Chemical modifications of RNA molecules regulate both RNA metabolism and fate. The deposition and function of these modifications are mediated by the actions of writer, reader, and eraser proteins. At the cellular level, RNA modifications regulate several cellular processes including cell death, proliferation, senescence, differentiation, migration, metabolism, autophagy, the DNA damage response, and liquid-liquid phase separation. Emerging evidence demonstrates that RNA modifications play active roles in the physiology and etiology of multiple diseases due to their pervasive roles in cellular functions. Here, we will summarize recent advances in the regulatory and functional role of RNA modifications in these cellular functions, emphasizing the context-specific roles of RNA modifications in mammalian systems. As m6A is the best studied RNA modification in biological processes, this review will summarize the emerging advances on the diverse roles of m6A in cellular functions. In addition, we will also provide an overview for the cellular functions of other RNA modifications, including m5C and m1A. Furthermore, we will also discuss the roles of RNA modifications within the context of disease etiologies and highlight recent advances in the development of therapeutics that target RNA modifications. Elucidating these context-specific functions will increase our understanding of how these modifications become dysregulated during disease pathogenesis and may provide new opportunities for improving disease prevention and therapy by targeting these pathways.

https://www.frontiersin.org/articles/10.3389/fcell.2022.828683/pdf

Roles of RNA Modifications in Diverse Cellular Functions

Epigenetic regulation in fibrosis progress.

N 6-methyladenosine (m6A) modification of RNA is deposited by the methyltransferase complex consisting of Mettl3 and Mettl14 and erased by demethylase Fto and Alkbh5 and is involved in diverse biological processes. However, it remains largely unknown the specific function and mechanism of Fto in regulating adult neural stem cells (aNSCs). In the present study, utilizing a conditional knockout (cKO) mouse model, we show that the specific ablation of Fto in aNSCs transiently increases the proliferation of aNSCs and promotes neuronal differentiation both in vitro and in vivo, but in a long term, the specific ablation of Fto inhibits adult neurogenesis and neuronal development. Mechanistically, Fto deficiency results in a significant increase in m6A modification in Pdgfra and Socs5. The increased expression of Pdgfra and decreased expression of Socs5 synergistically promote the phosphorylation of Stat3. The modulation of Pdgfra and Socs5 can rescue the neurogenic deficits induced by Fto depletion. Our results together reveal an important function of Fto in regulating aNSCs through modulating Pdgfra/Socs5-Stat3 pathway.

Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice.

Tet (Ten eleven translocation) family proteins-mediated 5-hydroxymethylcytosine (5hmC) is highly enriched in the neuronal system, and is involved in diverse biological processes and diseases. However, the function of 5hmC in astrocyte remains completely unknown. In the present study, we show that Tet1 deficiency alters astrocyte morphology and impairs neuronal function. Specific deletion of Tet1 in astrocyte impairs learning and memory ability of mice. Using 5hmC high-throughput DNA sequencing and RNA sequencing, we present the distribution of 5hmC among genomic features in astrocyte and show that Tet1 deficiency induces differentially hydroxymethylated regions (DhMRs) and alters gene expression. Mechanistically, we found that Tet1 deficiency leads to the abnormal Ca2+ signaling by regulating the expression of GluA1, which can be rescued by ectopic GluA1. Collectively, our findings suggest that Tet1 plays important function in astrocyte physiology by regulating Ca2+ signaling.

/pdf/tet1-regulates-astrocyte-development-and-cognition-of-mice-35j1ysyzqm.pdf

Tet1 Regulates Astrocyte Development and Cognition of Mice Through Modulating GluA1.

The ten-eleven translocation (Tet) family of dioxygenases convert 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) Previous studies have shown that 5hmC-mediated epigenetic modifications play essential roles in diverse biological processes and diseases Here, we show that Tet proteins and 5hmC display dynamic features during postnatal cardiac development and that Tet2 is the predominant dioxygenase present in heart Tet2 knockout results in abnormal cardiac function, progressive cardiac hypertrophy and fibrosis Mechanistically, Tet2 deficiency leads to reduced hydroxymethylation in the cardiac genome and alters the cardiac transcriptome Mechanistically, Tet2 loss leads to a decrease of Hspa1b expression, a regulator of the extracellular signal-regulated protein kinase (Erk) signaling pathway, which leads to over-activation of Erk signaling Acute Hspa1b knock down (KD) increased the phosphorylation of Erk and induced hypertrophy of cardiomyocytes, which could be blocked by Erk signaling inhibitor Consistently, ectopic expression of Hspa1b was able to rescue the deficits of cardiomyocytes induced by Tet2 depletion Taken together, our study's results reveal the important roles of Tet2-mediated DNA hydroxymethylation in cardiac development and function

Loss of Ten-Eleven Translocation 2 induces cardiac hypertrophy and fibrosis through modulating ERK signaling pathway.

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Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice.

Tet1 Regulates Astrocyte Development and Cognition of Mice Through Modulating GluA1.

Loss of Ten-Eleven Translocation 2 induces cardiac hypertrophy and fibrosis through modulating ERK signaling pathway.