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1.
Nat Genet ; 53(8): 1156-1165, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34211177

RESUMO

The most prevalent post-transcriptional mRNA modification, N6-methyladenosine (m6A), plays diverse RNA-regulatory roles, but its genetic control in human tissues remains uncharted. Here we report 129 transcriptome-wide m6A profiles, covering 91 individuals and 4 tissues (brain, lung, muscle and heart) from GTEx/eGTEx. We integrate these with interindividual genetic and expression variation, revealing 8,843 tissue-specific and 469 tissue-shared m6A quantitative trait loci (QTLs), which are modestly enriched in, but mostly orthogonal to, expression QTLs. We integrate m6A QTLs with disease genetics, identifying 184 GWAS-colocalized m6A QTL, including brain m6A QTLs underlying neuroticism, depression, schizophrenia and anxiety; lung m6A QTLs underlying expiratory flow and asthma; and muscle/heart m6A QTLs underlying coronary artery disease. Last, we predict novel m6A regulators that show preferential binding in m6A QTLs, protein interactions with known m6A regulators and expression correlation with the m6A levels of their targets. Our results provide important insights and resources for understanding both cis and trans regulation of epitranscriptomic modifications, their interindividual variation and their roles in human disease.


Assuntos
Adenosina/análogos & derivados , Encéfalo/fisiologia , Pulmão/fisiologia , Músculo Esquelético/fisiologia , Locos de Características Quantitativas , Adenosina/genética , Adenosina/metabolismo , Estudo de Associação Genômica Ampla , Coração/fisiologia , Humanos , Metilação , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/genética , Reprodutibilidade dos Testes
2.
Mol Cell ; 77(2): 426-440.e6, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31676230

RESUMO

N6-methyladenosine (m6A), the most abundant internal mRNA modification, and N6,2'-O-dimethyladenosine (m6Am), found at the first-transcribed nucleotide, are two reversible epitranscriptomic marks. However, the profiles and distribution patterns of m6A and m6Am across human and mouse tissues are poorly characterized. Here, we report the m6A and m6Am methylome through profiling of 43 human and 16 mouse tissues and demonstrate strongest tissue specificity for the brain tissues. A small subset of tissue-specific m6A peaks can also readily classify tissue types. The overall m6A and m6Am level is partially correlated with the expression level of their writers and erasers. Additionally, the m6A-containing regions are enriched for SNPs. Furthermore, cross-species analysis revealed that species rather than tissue type 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.


Assuntos
RNA Mensageiro/genética , Animais , Encéfalo/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Células HT29 , Células HeLa , Humanos , Células Jurkat , Células K562 , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Polimorfismo de Nucleotídeo Único/genética
3.
RNA ; 24(11): 1437-1442, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30131401

RESUMO

N 1-methyladenosine was recently reported to be a chemical modification in mRNA. However, while we identified hundreds of m1A sites in the human transcriptome in a previous work, others have detected only nine sites in cytosolic and mitochondrial mRNAs. Herein, we provide additional evidence that hundreds of m1A sites are present in the human transcriptome. Moreover, we show that both the improper bioinformatic tools and the poor quality of sequencing data in a previous study led to the failure in identifying the majority of m1A sites. Our analysis hence provides an explanation of the divergence in the prevalence of this newly discovered mRNA mark.


Assuntos
Adenosina , RNA Mensageiro/genética , Transcriptoma , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Metilação , Processamento Pós-Transcricional do RNA , RNA Mensageiro/química , Sítio de Iniciação de Transcrição
4.
Curr Opin Chem Biol ; 45: 179-186, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30007213

RESUMO

Chemical modifications to rRNA, tRNA and mRNA provide a new regulatory layer of gene expression, which is termed as the `epitranscriptome'. N1-methyladenosine (m1A), first characterized more than 50 years ago, is a well-known modification in rRNA and tRNA. m1A in these abundant non-coding RNAs plays important roles in maintaining their biological functions. Recent studies also reveal that m1A is present in both nuclear-encoded and mitochondrial-encoded mRNA and is dynamically regulated by environmental and developmental conditions; m1A is found in a subset of nuclear-encoded long non-coding RNAs as well. Finally, we also discuss the potential challenges of identifying m1A modification in the human transcriptome.


Assuntos
Adenosina/análogos & derivados , Epigênese Genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mitocondrial/genética , RNA Nuclear/genética , Transcriptoma , Adenosina/análise , Adenosina/genética , Animais , Humanos , Metilação , RNA Longo não Codificante/química , RNA Mensageiro/química , RNA Mitocondrial/química , RNA Nuclear/química
5.
Mol Cell ; 68(5): 993-1005.e9, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29107537

RESUMO

Gene expression can be post-transcriptionally regulated via dynamic and reversible RNA modifications. N1-methyladenosine (m1A) is a recently identified mRNA modification; however, little is known about its precise location and biogenesis. Here, we develop a base-resolution m1A profiling method, based on m1A-induced misincorporation during reverse transcription, and report distinct classes of m1A methylome in the human transcriptome. m1A in 5' UTR, particularly those at the mRNA cap, associate with increased translation efficiency. A different, small subset of m1A exhibit a GUUCRA tRNA-like motif, are evenly distributed in the transcriptome, and are dependent on the methyltransferase TRMT6/61A. Additionally, we show that m1A is prevalent in the mitochondrial-encoded transcripts. Manipulation of m1A level via TRMT61B, a mitochondria-localizing m1A methyltransferase, demonstrates that m1A in mitochondrial mRNA interferes with translation. Collectively, our approaches reveal distinct classes of m1A methylome and provide a resource for functional studies of m1A-mediated epitranscriptomic regulation.


Assuntos
Adenosina/análogos & derivados , Núcleo Celular/metabolismo , Mitocôndrias/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/metabolismo , RNA de Transferência/metabolismo , Imagem Individual de Molécula/métodos , Regiões 5' não Traduzidas , Adenosina/metabolismo , Células HEK293 , Humanos , Proteínas Mitocondriais/biossíntese , Proteínas Mitocondriais/genética , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Biossíntese de Proteínas , Capuzes de RNA , Interferência de RNA , RNA Mensageiro/genética , RNA de Transferência/genética , Transfecção , tRNA Metiltransferases/genética , tRNA Metiltransferases/metabolismo
7.
Nat Methods ; 14(1): 23-31, 2016 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-28032622

RESUMO

In recent years, major breakthroughs in RNA-modification-mediated regulation of gene expression have been made, leading to the emerging field of epitranscriptomics.Our understanding of the distribution, regulation and function of these dynamic RNA modifications is based on sequencing technologies. In this Review, we focus on the major mRNA modifications in the transcriptome of eukaryotic cells: N6-methyladenosine, N6, 2'-O-dimethyladenosine, 5-methylcytidine, 5-hydroxylmethylcytidine, inosine, pseudouridine and N1-methyladenosine. We discuss the sequencing technologies used to profile these epitranscriptomic marks, including scale, resolution, quantitative feature, pre-enrichment capability and the corresponding bioinformatics tools. We also discuss the challenges of epitranscriptome profiling and highlight the prospect of future detection tools. We aim to guide the choice of different detection methods and inspire new ideas in RNA biology.


Assuntos
Epigênese Genética/genética , Epigenômica , Sequenciamento de Nucleotídeos em Larga Escala , RNA/química , RNA/genética , Transcriptoma/genética , Animais , Humanos
8.
Angew Chem Int Ed Engl ; 55(46): 14246-14249, 2016 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-27736024

RESUMO

Cisplatin, one of the most widely used anticancer drugs, crosslinks DNA and ultimately induces cell death. However, the genomic pattern of cisplatin-DNA adducts has remained unknown owing to the lack of a reliable and sensitive genome-wide method. Herein we present "cisplatin-seq" to identify genome-wide cisplatin crosslinking sites at base resolution. Cisplatin-seq reveals that mitochondrial DNA is a preferred target of cisplatin. For nuclear genomes, cisplatin-DNA adducts are enriched within promoters and regions harboring transcription termination sites. While the density of GG dinucleotides determines the initial crosslinking of cisplatin, binding of proteins to the genome largely contributes to the accumulative pattern of cisplatin-DNA adducts.


Assuntos
Antineoplásicos/química , Cisplatino/química , Adutos de DNA/análise , DNA Mitocondrial/química , Imunoprecipitação da Cromatina , Cisplatino/análise , Reparo do DNA , Genoma Humano , Proteína HMGB1/química , Proteína HMGB1/metabolismo , Células HeLa , Humanos , Análise de Sequência de DNA
9.
Nat Chem Biol ; 12(5): 311-6, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26863410

RESUMO

N(1)-Methyladenosine (m(1)A) is a prevalent post-transcriptional RNA modification, yet little is known about its abundance, topology and dynamics in mRNA. Here, we show that m(1)A is prevalent in Homo sapiens mRNA, which shows an m(1)A/A ratio of ∼0.02%. We develop the m(1)A-ID-seq technique, based on m(1)A immunoprecipitation and the inherent ability of m(1)A to stall reverse transcription, as a means for transcriptome-wide m(1)A profiling. m(1)A-ID-seq identifies 901 m(1)A peaks (from 600 genes) in mRNA and noncoding RNA and reveals a prominent feature, enrichment in the 5' untranslated region of mRNA transcripts, that is distinct from the pattern for N(6)-methyladenosine, the most abundant internal mammalian mRNA modification. Moreover, m(1)A in mRNA is reversible by ALKBH3, a known DNA/RNA demethylase. Lastly, we show that m(1)A methylation responds dynamically to stimuli, and we identify hundreds of stress-induced m(1)A sites. Collectively, our approaches allow comprehensive analysis of m(1)A modification and provide tools for functional studies of potential epigenetic regulation via the reversible and dynamic m(1)A methylation.


Assuntos
Adenosina/análogos & derivados , Transcriptoma , Adenosina/metabolismo , Homólogo AlkB 3 da Dioxigenase Dependente de alfa-Cetoglutarato , Anticorpos , Sequência de Bases , Linhagem Celular , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Dioxigenases/genética , Dioxigenases/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Metilação , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Brief Bioinform ; 16(1): 45-58, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24307685

RESUMO

Transcription factors (TFs) and microRNAs (miRNAs) can jointly regulate target gene expression in the forms of feed-forward loops (FFLs) or feedback loops (FBLs). These regulatory loops serve as important motifs in gene regulatory networks and play critical roles in multiple biological processes and different diseases. Major progress has been made in bioinformatics and experimental study for the TF and miRNA co-regulation in recent years. To further speed up its identification and functional study, it is indispensable to make a comprehensive review. In this article, we summarize the types of FFLs and FBLs and their identified methods. Then, we review the behaviors and functions for the experimentally identified loops according to biological processes and diseases. Future improvements and challenges are also discussed, which includes more powerful bioinformatics approaches and high-throughput technologies in TF and miRNA target prediction, and the integration of networks of multiple levels.


Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs/genética , Fatores de Transcrição/genética , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Retroalimentação Fisiológica , Humanos
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