Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

RNA carries a diverse array of chemical modifications that play important roles in the regulation of gene expression. N6 -methyladenosine (m6 A), installed onto mRNA by the METTL3/METTL14 methyltransferase complex, is the most prevalent mRNA modification. m6 A methylation regulates gene expression by influencing numerous aspects of mRNA metabolism, including pre-mRNA processing, nuclear export, decay, and translation. The importance of m6 A methylation as a mode of post-transcriptional gene expression regulation is evident in the crucial roles m6 A-mediated gene regulation plays in numerous physiological and pathophysiological processes. Here, we review current knowledge on the mechanisms by which m6 A exerts its functions and discuss recent advances that underscore the multifaceted role of m6 A in the regulation of gene expression. We highlight advances in our understanding of the regulation of m6 A deposition on mRNA and its context-dependent effects on mRNA decay and translation, the role of m6 A methylation of non-coding chromosomal-associated RNA species in regulating transcription, and the activities of the RNA demethylase FTO on diverse substrates. We also discuss emerging evidence for the therapeutic potential of targeting m6 A regulators in disease.

m 6 A RNA methylation: from mechanisms to therapeutic potential

Liver cancer is a common cancer worldwide. Although the etiological factors of liver carcinogenesis are well defined, the underlying molecular mechanisms remain largely elusive. Epigenetic deregulations, such as aberrant DNA methylation and histone modifications, play a critical role in liver carcinogenesis. Analogous to DNA and core histone proteins, reversible chemical modifications on mRNA have recently been recognized as important regulatory mechanisms to control gene expression. N6-methyladenosine (m6A) is the most prevalent internal mRNA modification in mammalian cells. m6A modification is important for controlling many cellular and biological processes. Deregulation of m6A modification has been recently implicated in human carcinogenesis, including liver cancer. In this review, we summarize the recent findings on m6A regulation and its biological impacts in normal and cancer cells. We will focus on the deregulation of m6A modification and m6A regulators in liver diseases and liver cancers. We will highlight the clinical relevance of m6A deregulation in liver cancer. We will also discuss the potential of exploiting m6A modification for cancer diagnosis and therapeutics.

/pdf/the-emerging-roles-of-n6-methyladenosine-m6a-deregulation-in-1ne01jl7j0.pdf

The emerging roles of N6-methyladenosine (m6A) deregulation in liver carcinogenesis

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.

/pdf/mapping-the-epigenetic-modifications-of-dna-and-rna-1hzqttre6z.pdf

Mapping the epigenetic modifications of DNA and RNA

MicroRNAs (miRNAs) are approximately 22-nucleotide-long, small non-coding RNAs that post-transcriptionally regulate gene expression. The biogenesis of miRNAs involves multiple steps, including the transcription of primary miRNAs (pri-miRNAs), nuclear Drosha-mediated processing, cytoplasmic Dicer-mediated processing, and loading onto Argonaute (Ago) proteins. Further, miRNAs control diverse biological and pathological processes via the silencing of target mRNAs. This review summarizes recent findings regarding the quantitative aspects of miRNA homeostasis, including Drosha-mediated pri-miRNA processing, Ago-mediated asymmetric miRNA strand selection, and modifications of miRNA pathway components, as well as the roles of RNA modifications (epitranscriptomics), epigenetics, transcription factor circuits, and super-enhancers in miRNA regulation. These recent advances have facilitated a system-level understanding of miRNA networks, as well as the improvement of RNAi performance for both gene-specific targeting and genome-wide screening. The comprehensive understanding and modeling of miRNA biogenesis and function have been applied to the design of synthetic gene circuits. In addition, the relationships between miRNA genes and super-enhancers provide the molecular basis for the highly biased cell type-specific expression patterns of miRNAs and the evolution of miRNA–target connections, while highlighting the importance of alterations of super-enhancer-associated miRNAs in a variety of human diseases.

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis.

Landscape and Regulation of m6A and m6Am Methylome across Human and Mouse Tissues

N6-methyladenosine (m6A), the most abundant internal mRNA modification, and N6,2’-O-dimethyladenosine (m6Am), found at the first-transcribed nucleotide, are two examples of dynamic and reversible epitranscriptomic marks. However, the profiles and distribution patterns of m6A and m6Am across different human and mouse tissues are poorly characterized. Here we report the m6A and m6Am methylome through an extensive profiling of 42 human tissues and 16 mouse tissue samples. Globally, the m6A and m6Am peaks in non-brain tissues demonstrates mild tissue-specificity but are correlated in general, whereas the m6A and m6Am methylomes of brain tissues are clearly resolved from the non-brain tissues. Nevertheless, we identified a small subset of tissue-specific m6A peaks that can readily classify the tissue types. The number of m6A and m6Am peaks are partially correlated with the expression levels of their writers and erasers. In addition, them6A- and m6Am-containing regions are enriched for single nucleotide polymorphisms. Furthermore, cross-species analysis of m6A and m6Am methylomes revealed that species, rather than tissue types, is the primary determinant of methylation. Collectively, our study provides an in-depth resource for dissecting the landscape and regulation of the m6A and m6Am epitranscriptomic marks across mammalian tissues.

Landscape and Regulation of M 6 A and M 6 Am Methylome Across Human and Mouse Tissues

SUMMARY N6-methyladenosine (m6A), the most abundant internal mRNA modification, and N6,2’-O-dimethyladenosine (m6Am), found at the first-transcribed nucleotide, are two examples of dynamic and reversible epitranscriptomic marks. However, the profiles and distribution patterns of m6A and m6Am across different human and mouse tissues are poorly characterized. Here we report the m6A and m6Am methylome through an extensive profiling of 42 human tissues and 16 mouse tissue samples. Globally, the m6A and m6Am peaks in non-brain tissues demonstrates mild tissue-specificity but are correlated in general, whereas the m6A and m6Am methylomes of brain tissues are clearly resolved from the non-brain tissues. Nevertheless, we identified a small subset of tissue-specific m6A peaks that can readily classify the tissue types. The number of m6A and m6Am peaks are partially correlated with the expression levels of their writers and erasers. In addition, the m6A- and m6Am-containing regions are enriched for single nucleotide polymorphisms. Furthermore, cross-species analysis of m6A and m6Am methylomes revealed that species, rather than tissue types, is the primary determinant of methylation. Collectively, our study provides an in-depth resource for dissecting the landscape and regulation of the m6A and m6Am epitranscriptomic marks across mammalian tissues.

https://www.biorxiv.org/content/biorxiv/early/2019/05/08/632000.full.pdf

Mingchang Zhang

Papers

Landscape and Regulation of m6A and m6Am Methylome across Human and Mouse Tissues

Landscape and Regulation of M 6 A and M 6 Am Methylome Across Human and Mouse Tissues

Landscape and regulation of m6A and m6Am methylome across human and mouse tissues