ABSTRACT
The occurrence of gastric cancer is closely related to environmental, genetic, and epigenetic factors. Currently, RNA modification is a research frontier and hotspot in the field of epigenetics. With the advancements in analytical chemistry and high-throughput sequencing technologies, new technologies and methods of exploring RNA modification are constantly being presented. Numerous studies have confirmed the involvement of RNA modifications in the occurrence and development of various diseases. Recent studies have shown that RNA modifications such as m6A, m5C, and ac4C regulate the malignant progression of various tumors, including gastric cancer, liver cancer, colorectal cancer, and leukemia. This article systematically reviews the research status and mechanism of different RNA modifications in the occurrence and development of gastric cancer, as well as discusses its potential value in the diagnosis and treatment of gastric cancer.
ABSTRACT
In neuronal system, epigenetic modifications are essential for neuronal development, the fate determination of neural stem cells and neuronal function. The dysfunction of epigenetic regulation is closely related to occurrence and development of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease. Abnormally elevated DNA methylation inhibits the expression of some DNA repair-related genes and affects the progression of Huntington's disease. In the brain of Alzheimer's disease patients, the levels of H3K27ac and H3K9ac histone modifications increased. In addition, the alteration of RNA methylation in animal models of Alzheimer's disease and Parkinson's disease showed discrepancy trends. Therefore, epigenetic modifications may serve as potential therapeutic targets for neurodegenerative diseases. Here, we summarize the recent progress of the roles of epigenetic modifications in neurodegenerative diseases.
Subject(s)
Animals , Humans , DNA Methylation , Epigenesis, Genetic , Neurodegenerative Diseases/genetics , Parkinson Disease/genetics , Protein Processing, Post-TranslationalABSTRACT
N6-methyladenosine (m6A) is the most prevalent and abundant post-transcriptional RNA modification in eukaryotes. m6A is a dy-namic and reversible process catalyzed by m6A methyltransferase complex and demethylase. m6A is involved in the regulations of gene expres-sion and biological processes. Recently, researches have discovered that m6A plays a vital role in the differentiation and regulation of immune cells, which could provide a new idea for the research and therapy of immune-related diseases. The present article reviews the recent progresses of m6A in immunoregulation.
ABSTRACT
Over 17 and 160 types of chemical modifications have been identified in DNA and RNA, respectively. The interest in understanding the various biological functions of DNA and RNA modifications has lead to the cutting-edged fields of epigenomics and epitranscriptomics. Developing chemical and biological tools to detect specific modifications in the genome or transcriptome has greatly facilitated their study. Here, we review the recent technological advances in this rapidly evolving field. We focus on high-throughput detection methods and biological findings for these modifications, and discuss questions to be addressed as well. We also summarize third-generation sequencing methods, which enable long-read and single-molecule sequencing of DNA and RNA modification.
Subject(s)
Animals , Humans , DNA/metabolism , DNA Methylation , Epigenesis, Genetic , Epigenomics , RNA/metabolism , TranscriptomeABSTRACT
N-methyladenosine (mA), a ubiquitous RNA modification, is installed by METTL3-METTL14 complex. The structure of the heterodimeric complex between the methyltransferase domains (MTDs) of METTL3 and METTL14 has been previously determined. However, the MTDs alone possess no enzymatic activity. Here we present the solution structure for the zinc finger domain (ZFD) of METTL3, the inclusion of which fulfills the methyltransferase activity of METTL3-METTL14. We show that the ZFD specifically binds to an RNA containing 5'-GGACU-3' consensus sequence, but does not to one without. The ZFD thus serves as the target recognition domain, a structural feature previously shown for DNA methyltransferases, and cooperates with the MTDs of METTL3-METTL14 for catalysis. However, the interaction between the ZFD and the specific RNA is extremely weak, with the binding affinity at several hundred micromolar under physiological conditions. The ZFD contains two CCCH-type zinc fingers connected by an anti-parallel β-sheet. Mutational analysis and NMR titrations have mapped the functional interface to a contiguous surface. As a division of labor, the RNA-binding interface comprises basic residues from zinc finger 1 and hydrophobic residues from β-sheet and zinc finger 2. Further we show that the linker between the ZFD and MTD of METTL3 is flexible but partially folded, which may permit the cooperation between the two domains during catalysis. Together, the structural characterization of METTL3 ZFD paves the way to elucidate the atomic details of the entire process of RNA mA modification.
ABSTRACT
N-methyladenosine (mA) is the most common post-transcriptional RNA modification throughout the transcriptome, affecting fundamental aspects of RNA metabolism. mA modification could be installed by mA "writers" composed of core catalytic components (METTL3/METTL14/WTAP) and newly defined regulators and removed by mA "erasers" (FTO and ALKBH5). The function of mA is executed by mA "readers" that bind to mA directly (YTH domain-containing proteins, eIF3 and IGF2BPs) or indirectly (HNRNPA2B1). In the past few years, advances in mA modulators ("writers," "erasers," and "readers") have remarkably renewed our understanding of the function and regulation of mA in different cells under normal or disease conditions. However, the mechanism and the regulatory network of mA are still largely unknown. Moreover, investigations of the mA physiological roles in human diseases are limited. In this review, we summarize the recent advances in mA research and highlight the functional relevance and importance of mA modification in in vitro cell lines, in physiological contexts, and in cancers.
Subject(s)
Humans , Adenosine , Metabolism , Cell Differentiation , Physiology , Neoplasms , Metabolism , RNA , Metabolism , RNA Processing, Post-TranscriptionalABSTRACT
Like protein and DNA, different types of RNA molecules undergo various modifications. Accumulating evidence suggests that these RNA modifications serve as sophisticated codes to mediate RNA behaviors and many important biological functions. N-methyladenosine (mA) is the most abundant internal RNA modification found in a variety of eukaryotic RNAs, including but not limited to mRNAs, tRNAs, rRNAs, and long non-coding RNAs (lncRNAs). In mammalian cells, mA can be incorporated by a methyltransferase complex and removed by demethylases, which ensures that the mA modification is reversible and dynamic. Moreover, mA is recognized by the YT521-B homology (YTH) domain-containing proteins, which subsequently direct different complexes to regulate RNA signaling pathways, such as RNA metabolism, RNA splicing, RNA folding, and protein translation. Herein, we summarize the recent progresses made in understanding the molecular mechanisms underlying the mA recognition by YTH domain-containing proteins, which would shed new light on mA-specific recognition and provide clues to the future identification of reader proteins of many other RNA modifications.
Subject(s)
Animals , Humans , Adenosine , Chemistry , Metabolism , Protein Binding , Protein Domains , RNA , Chemistry , Metabolism , RNA-Binding Proteins , Chemistry , MetabolismABSTRACT
More than 100 modifications have been found in RNA. Analogous to epigenetic DNA methylation, epitranscriptomic modifications can be written, read, and erased by a complex network of proteins. Apart from N-methyladenosine (mA), N-methyladenosine (mA) has been found as a reversible modification in tRNA and mRNA. mA occurs at positions 9, 14, and 58 of tRNA, with mA58 being critical for tRNA stability. Other than the hundreds of mA sites in mRNA and long non-coding RNA transcripts, transcriptome-wide mapping of mA also identifies >20 mA sites in mitochondrial genes. mA in the coding region of mitochondrial transcripts can inhibit the translation of the corresponding proteins. In this review, we summarize the current understanding of mA in mRNA and tRNA, covering high-throughput sequencing methods developed for mA methylome, mA-related enzymes (writers and erasers), as well as its functions in mRNA and tRNA.