RESUMEN
Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus microglial transcriptomes and epigenomes across 443 human subjects and diverse Alzheimer's disease (AD) pathological phenotypes. We annotate 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. We identify 1,542 AD-differentially-expressed genes, including both microglia-state-specific and disease-stage-specific alterations. By integrating epigenomic, transcriptomic, and motif information, we infer upstream regulators of microglial cell states, gene-regulatory networks, enhancer-gene links, and transcription-factor-driven microglial state transitions. We demonstrate that ectopic expression of our predicted homeostatic-state activators induces homeostatic features in human iPSC-derived microglia-like cells, while inhibiting activators of inflammation can block inflammatory progression. Lastly, we pinpoint the expression of AD-risk genes in microglial states and differential expression of AD-risk genes and their regulators during AD progression. Overall, we provide insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution.
Asunto(s)
Enfermedad de Alzheimer , Microglía , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Regulación de la Expresión Génica , Inflamación/patología , Microglía/metabolismo , Factores de Transcripción/metabolismo , Transcriptoma , EpigenomaRESUMEN
Recent work has identified dozens of non-coding loci for Alzheimer's disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile epigenomic and transcriptomic landscapes of 850,000 nuclei from prefrontal cortexes of 92 individuals with and without AD to build a map of the brain regulome, including epigenomic profiles, transcriptional regulators, co-accessibility modules, and peak-to-gene links in a cell-type-specific manner. We develop methods for multimodal integration and detecting regulatory modules using peak-to-gene linking. We show AD risk loci are enriched in microglial enhancers and for specific TFs including SPI1, ELF2, and RUNX1. We detect 9,628 cell-type-specific ATAC-QTL loci, which we integrate alongside peak-to-gene links to prioritize AD variant regulatory circuits. We report differential accessibility of regulatory modules in late AD in glia and in early AD in neurons. Strikingly, late-stage AD brains show global epigenome dysregulation indicative of epigenome erosion and cell identity loss.
Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Regulación de la Expresión Génica , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Encéfalo/patología , Epigenoma , Epigenómica , Estudio de Asociación del Genoma CompletoRESUMEN
5-methylcytosine (m5C) is a prevalent RNA modification crucial for gene expression regulation. However, accurate and sensitive m5C sites identification remains challenging due to severe RNA degradation and reduced sequence complexity during bisulfite sequencing (BS-seq). Here, we report m5C-TAC-seq, a bisulfite-free approach combining TET-assisted m5C-to-f5C oxidation with selective chemical labeling, therefore enabling direct base-resolution m5C detection through pre-enrichment and C-to-T transitions at m5C sites. With m5C-TAC-seq, we comprehensively profiled the m5C methylomes in human and mouse cells, identifying a substantially larger number of confident m5C sites. Through perturbing potential m5C methyltransferases, we deciphered the responsible enzymes for most m5C sites, including the characterization of NSUN5's involvement in mRNA m5C deposition. Additionally, we characterized m5C dynamics during mESC differentiation. Notably, the mild reaction conditions and preservation of nucleotide composition in m5C-TAC-seq allow m5C detection in chromatin-associated RNAs. The accurate and robust m5C-TAC-seq will advance research into m5C methylation functional investigation.
Asunto(s)
5-Metilcitosina , Sulfitos , Transcriptoma , 5-Metilcitosina/metabolismo , 5-Metilcitosina/química , Animales , Humanos , Ratones , Sulfitos/química , Metiltransferasas/metabolismo , Metiltransferasas/genética , Perfilación de la Expresión Génica/métodos , Diferenciación CelularRESUMEN
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.
Asunto(s)
ARN Mensajero/genética , Animales , Encéfalo/fisiología , Línea Celular , Línea Celular Tumoral , Células HEK293 , Células HT29 , Células HeLa , Humanos , Células Jurkat , Células K562 , Masculino , Metilación , Ratones , Ratones Endogámicos C57BL , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
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.
Asunto(s)
Adenosina/análogos & derivados , Núcleo Celular/metabolismo , Mitocondrias/metabolismo , Procesamiento Postranscripcional del ARN , ARN Mensajero/metabolismo , ARN de Transferencia/metabolismo , Imagen Individual de Molécula/métodos , Regiones no Traducidas 5' , Adenosina/metabolismo , Células HEK293 , Humanos , Proteínas Mitocondriales/biosíntesis , Proteínas Mitocondriales/genética , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Biosíntesis de Proteínas , Caperuzas de ARN , Interferencia de ARN , ARN Mensajero/genética , ARN de Transferencia/genética , Transfección , ARNt Metiltransferasas/genética , ARNt Metiltransferasas/metabolismoRESUMEN
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.
Asunto(s)
Adenosina , ARN Mensajero/genética , Transcriptoma , Humanos , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Metilación , Procesamiento Postranscripcional del ARN , ARN Mensajero/química , Sitio de Iniciación de la TranscripciónRESUMEN
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.
Asunto(s)
Epigénesis Genética/genética , Epigenómica , Secuenciación de Nucleótidos de Alto Rendimiento , ARN/química , ARN/genética , Transcriptoma/genética , Animales , HumanosRESUMEN
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 â¼0.02%. 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.
Asunto(s)
Adenosina/análogos & derivados , Transcriptoma , Adenosina/metabolismo , Dioxigenasa Dependiente de Alfa-Cetoglutarato, Homólogo 3 de AlkB , Anticuerpos , Secuencia de Bases , Línea Celular , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Dioxigenasas/genética , Dioxigenasas/metabolismo , Regulación de la Expresión Génica/fisiología , Humanos , Metilación , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
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.
Asunto(s)
Regulación de la Expresión Génica , Redes Reguladoras de Genes , MicroARNs/genética , Factores de Transcripción/genética , Animales , Diferenciación Celular/genética , Proliferación Celular/genética , Retroalimentación Fisiológica , HumanosRESUMEN
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.
Asunto(s)
Antineoplásicos/química , Cisplatino/química , Aductos de ADN/análisis , ADN Mitocondrial/química , Inmunoprecipitación de Cromatina , Cisplatino/análisis , Reparación del ADN , Genoma Humano , Proteína HMGB1/química , Proteína HMGB1/metabolismo , Células HeLa , Humanos , Análisis de Secuencia de ADNRESUMEN
N6-methyladenosine (m6A) has been established as the most prevalent chemical modification in message RNA (mRNA), playing an essential role in determining the fate of RNA molecules. Dysregulation of m6A has been revealed to lead to abnormal physiological conditions and cause various types of human diseases. Recent studies have delineated the genetic regulatory maps for m6A methylation by mapping the quantitative trait loci of m6A (m6A-QTLs), thereby building up the regulatory circuits linking genetic variants, m6A, and human complex traits. Here, we review the recent discoveries concerning the genetic regulatory maps of m6A, describing the methodological and technical details of m6A-QTL identification, and introducing the key findings of the cis- and trans-acting drivers of m6A. We further delve into the tissue- and ethnicity-specificity of m6A-QTL, the association with other molecular phenotypes in light of genetic regulation, the regulators underlying m6A genetics, and importantly, the functional roles of m6A in mediating human complex diseases. Lastly, we discuss potential research avenues that can accelerate the translation of m6A genetics studies toward the development of therapies for human genetic diseases.
Asunto(s)
Adenosina , Sitios de Carácter Cuantitativo , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Metilación , Regulación de la Expresión Génica , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN/genética , ARN/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Metilación de ARNRESUMEN
Wilms tumor-1(WT1) is a crucial transcription factor that regulates podocyte development. However, the epigenomic mechanism underlying the function of WT1 during podocyte development has yet to be fully elucidated. Here, single-cell chromatin accessibility and gene expression maps of foetal kidneys and kidney organoids are generated. Functional implications of WT1-targeted genes, which are crucial for the development of podocytes and the maintenance of their structure, including BMPER/PAX2/MAGI2 that regulates WNT signaling pathway, MYH9 that maintains actin filament organization and NPHS1 that modulates cell junction assembly are identified. To further illustrate the functional importance of WT1-mediated transcriptional regulation during podocyte development, cultured and implanted patient-derived kidney organoids derived from the Induced Pluripotent Stem Cell (iPSCs) of a patient with a heterozygous missense mutation in WT1 are generated. Results from single-cell RNA sequencing (scRNA-seq) and functional assays confirm that the WT1 mutation leads to delays in podocyte development and causes damage to cell structures, due to its failure to activate the targeting genes MAGI2, MYH9, and NPHS1. Notably, correcting the mutation in the patient iPSCs using CRISPR-Cas9 gene editing rescues the podocyte phenotype. Collectively, this work elucidates the WT1-related epigenomic landscape with respect to human podocyte development and identifies the disease-causing role of a WT1 mutation.
Asunto(s)
Organoides , Podocitos , Proteínas WT1 , Podocitos/metabolismo , Humanos , Proteínas WT1/genética , Proteínas WT1/metabolismo , Organoides/metabolismo , Mutación/genética , Riñón/metabolismo , Células Madre Pluripotentes Inducidas/metabolismoRESUMEN
Bisphenol A (BPA) and its substitute fluorene-9-bisphenol (BHPF) are used in consumer products; however, their toxic effects on intestinal epithelium remain largely unknown. In this study, we combined intestinal organoids and single-cell RNA sequencing to investigate the impact of BPA and BHPF exposure on intestinal cell composition, differentiation, and function. Both compounds inhibited the growth of small intestinal organoids, with BHPF exhibiting a more potent inhibitory effect. BPA and BHPF did not significantly alter the overall cell type composition; however, they led to different alterations in cell-cell communications. Gene Ontology enrichment analysis showed that BPA and BHPF exposures affected various biological processes, such as glutathione transferase activity, antioxidant activity, and lipid metabolism, in cell type-specific and compound-dependent manners. Trajectory analysis demonstrated that BPA and BHPF altered the differentiation trajectory of the intestinal cells. To further connect the cellular mechanism to the phenotypic impact in vivo, we constructed a mouse model exposed to BPA or BHPF and observed significant alterations in intestinal morphology, including reduced crypt depth and villus length and impaired stem cell proliferation and self-renewal. These results provide novel insights into the cell type-specific effects of BPA and BHPF on the intestinal epithelium and highlight the potential risks of exposure to these compounds. Our findings underscore the importance of evaluating the safety of BPA substitutes and contribute to a better understanding of the effects of environmental chemicals on gut health.
RESUMEN
G-quadruplexes (G4s) are atypical nucleic acid structures involved in basic human biological processes and are regulated by small molecules. To date, pyridostatin and its derivatives [e.g., PyPDS (4-(2-aminoethoxy)-N 2,N 6-bis(4-(2-(pyrrolidin-1-yl) ethoxy) quinolin-2-yl) pyridine-2,6-dicarboxamide)] are the most widely used G4-binding small molecules and considered to have the best G4 specificity, which provides a new option for the development of cisplatin-binding DNA. By combining PyPDS with cisplatin and its analogs, we synthesize three platinum complexes, named PyPDSplatins. We found that cisplatin with PyPDS (CP) exhibits stronger specificity for covalent binding to G4 domains even in the presence of large amounts of dsDNA compared with PyPDS either extracellularly or intracellularly. Multiomics analysis reveals that CP can effectively regulate G4 functions, directly damage G4 structures, activate multiple antitumor signaling pathways, including the typical cGAS-STING pathway and AIM2-ASC pathway, trigger a strong immune response and lead to potent antitumor effects. These findings reflect that cisplatin-conjugated specific G4 targeting groups have antitumor mechanisms different from those of classic cisplatin and provide new strategies for the antitumor immunity of metals.
RESUMEN
Crosstalk between N6-methyladenosine (m6A) and epigenomes is crucial for gene regulation, but its regulatory directionality and disease significance remain unclear. Here, we utilize quantitative trait loci (QTLs) as genetic instruments to delineate directional maps of crosstalk between m6A and two epigenomic traits, DNA methylation (DNAme) and H3K27ac. We identify 47 m6A-to-H3K27ac and 4,733 m6A-to-DNAme and, in the reverse direction, 106 H3K27ac-to-m6A and 61,775 DNAme-to-m6A regulatory loci, with differential genomic location preference observed for different regulatory directions. Integrating these maps with complex diseases, we prioritize 20 genome-wide association study (GWAS) loci for neuroticism, depression, and narcolepsy in brain; 1,767 variants for asthma and expiratory flow traits in lung; and 249 for coronary artery disease, blood pressure, and pulse rate in muscle. This study establishes disease regulatory paths, such as rs3768410-DNAme-m6A-asthma and rs56104944-m6A-DNAme-hypertension, uncovering locus-specific crosstalk between m6A and epigenomic layers and offering insights into regulatory circuits underlying human diseases.
Asunto(s)
Adenosina , Metilación de ADN , Epigenómica , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Epigenómica/métodos , Epigénesis Genética , Epigenoma/genética , Transcriptoma , Histonas/metabolismo , Histonas/genéticaRESUMEN
Genetic variants associated with complex traits are primarily noncoding, and their effects on gene-regulatory activity remain largely uncharacterized. To address this, we profile epigenomic variation of histone mark H3K27ac across 387 brain, heart, muscle and lung samples from Genotype-Tissue Expression (GTEx). We annotate 282 k active regulatory elements (AREs) with tissue-specific activity patterns. We identify 2,436 sex-biased AREs and 5,397 genetically influenced AREs associated with 130 k genetic variants (haQTLs) across tissues. We integrate genetic and epigenomic variation to provide mechanistic insights for disease-associated loci from 55 genome-wide association studies (GWAS), by revealing candidate tissues of action, driver SNPs and impacted AREs. Lastly, we build ARE-gene linking scores based on genetics (gLink scores) and demonstrate their unique ability to prioritize SNP-ARE-gene circuits. Overall, our epigenomic datasets, computational integration and mechanistic predictions provide valuable resources and important insights for understanding the molecular basis of human diseases/traits such as schizophrenia.
Asunto(s)
Epigenómica , Estudio de Asociación del Genoma Completo , Humanos , Sitios de Carácter Cuantitativo/genética , Genotipo , Redes Reguladoras de Genes , Polimorfismo de Nucleótido Simple/genética , Predisposición Genética a la EnfermedadRESUMEN
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.
Asunto(s)
Adenosina/análogos & derivados , Encéfalo/fisiología , Pulmón/fisiología , Músculo Esquelético/fisiología , Sitios de Carácter Cuantitativo , Adenosina/genética , Adenosina/metabolismo , Estudio de Asociación del Genoma Completo , Corazón/fisiología , Humanos , Metilación , Especificidad de Órganos , Polimorfismo de Nucleótido Simple , Procesamiento Postranscripcional del ARN , Proteínas de Unión al ARN/genética , Reproducibilidad de los ResultadosRESUMEN
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N1-methyladenosine methylation (m1A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m1A methylation in a subset of tRNA to increase PPARδ translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer.
Asunto(s)
Adenosina/análogos & derivados , Carcinoma Hepatocelular/patología , Colesterol/metabolismo , Proteínas de la Membrana/metabolismo , PPAR gamma/metabolismo , ARN de Transferencia/metabolismo , ARNt Metiltransferasas/metabolismo , Adenosina/química , Adenosina/metabolismo , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Autorrenovación de las Células , Modelos Animales de Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Proteínas de la Membrana/genética , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Tasa de Supervivencia , ARNt Metiltransferasas/genéticaRESUMEN
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.