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1.
Trends Biochem Sci ; 49(3): 199-207, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38071089

RESUMEN

Gene expression is a complex process requiring many control mechanisms to achieve a desired phenotype. DNA accessibility within chromatin is well established as an important determinant of gene expression. By contrast, while mRNA also associates with a complement of proteins, the exact nature of messenger ribonucleoprotein (mRNP) packaging and its functional relevance is not as clear. Recent reports indicate that exon junction complex (EJC)-mediated mRNP packaging renders exon junction-proximal regions inaccessible for m6A methylation, and that EJCs reside within the inaccessible interior of globular transcription and export (TREX) complex-associated nuclear mRNPs. We propose that 'mRNA accessibility' within mRNPs is an important determinant of gene expression that may modulate the specificity of a broad array of regulatory processes including but not limited to m6A methylation.


Asunto(s)
Núcleo Celular , Ribonucleoproteínas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Núcleo Celular/metabolismo , Expresión Génica
2.
Mol Cell ; 71(6): 973-985.e5, 2018 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-30197295

RESUMEN

FTO, the first RNA demethylase discovered, mediates the demethylation of internal N6-methyladenosine (m6A) and N6, 2-O-dimethyladenosine (m6Am) at the +1 position from the 5' cap in mRNA. Here we demonstrate that the cellular distribution of FTO is distinct among different cell lines, affecting the access of FTO to different RNA substrates. We find that FTO binds multiple RNA species, including mRNA, snRNA, and tRNA, and can demethylate internal m6A and cap m6Am in mRNA, internal m6A in U6 RNA, internal and cap m6Am in snRNAs, and N1-methyladenosine (m1A) in tRNA. FTO-mediated demethylation has a greater effect on the transcript levels of mRNAs possessing internal m6A than the ones with cap m6Am in the tested cells. We also show that FTO can directly repress translation by catalyzing m1A tRNA demethylation. Collectively, FTO-mediated RNA demethylation occurs to m6A and m6Am in mRNA and snRNA as well as m1A in tRNA.


Asunto(s)
Adenosina/análogos & derivados , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/fisiología , Células 3T3-L1 , Adenosina/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Animales , Núcleo Celular , Citoplasma , Desmetilación , Expresión Génica/genética , Células HEK293 , Células HeLa , Humanos , Metilación , Ratones , Procesamiento Postranscripcional del ARN/fisiología , ARN Mensajero/metabolismo , ARN Nuclear Pequeño/metabolismo , ARN de Transferencia/metabolismo
3.
EMBO J ; 40(3): e105977, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33470439

RESUMEN

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.


Asunto(s)
Adenosina/análogos & derivados , ARN Mensajero/genética , ARN Mensajero/metabolismo , Adenosina/metabolismo , Animales , Humanos , Metiltransferasas/metabolismo , Procesamiento Postranscripcional del ARN
4.
Mol Cell ; 68(4): 773-785.e6, 2017 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-29129639

RESUMEN

Various factors differentially recognize trimethylated histone H3 lysine 4 (H3K4me3) near promoters, H3K4me2 just downstream, and promoter-distal H3K4me1 to modulate gene expression. This methylation "gradient" is thought to result from preferential binding of the H3K4 methyltransferase Set1/complex associated with Set1 (COMPASS) to promoter-proximal RNA polymerase II. However, other studies have suggested that location-specific cues allosterically activate Set1. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments show that H3K4 methylation patterns on active genes are not universal or fixed and change in response to both transcription elongation rate and frequency as well as reduced COMPASS activity. Fusing Set1 to RNA polymerase II results in H3K4me2 throughout transcribed regions and similarly extended H3K4me3 on highly transcribed genes. Tethered Set1 still requires histone H2B ubiquitylation for activity. These results show that higher-level methylations reflect not only Set1/COMPASS recruitment but also multiple rounds of transcription. This model provides a simple explanation for non-canonical methylation patterns at some loci or in certain COMPASS mutants.


Asunto(s)
Histonas/metabolismo , Modelos Biológicos , Saccharomyces cerevisiae/metabolismo , Schizosaccharomyces/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Metilación , Saccharomyces cerevisiae/genética , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ubiquitinación/fisiología
5.
Am J Pathol ; 193(11): 1627-1637, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37156326

RESUMEN

Age-related macular degeneration (AMD) is a progressive, degenerative retinal disease that is a leading cause of blindness globally. Although multiple risk factors have been identified regarding disease incidence and progression, including smoking, genetics, and diet, the understanding of AMD pathogenesis remains unclear. As such, primary prevention is lacking, and current treatments have limited efficacy. More recently, the gut microbiome has emerged as an influential player in various ocular pathologies. As mediators of metabolism and immune regulation, perturbations in gut microbiota may impart significant effects distally on the neuroretina and its adjacent tissues, termed the gut-retina axis. In this review, key studies over the past several decades are summarized, both in humans and in animal models, which shed insight on the relationships between the gut microbiome and retinal biology and their implications for AMD. The literature linking gut dysbiosis with AMD is examined, along with preclinical animal models and techniques apt for studying the role of gut microbiota in AMD pathogenesis, which include interactions with systemic inflammation, immune regulation, chorioretinal gene expression, and diet. As understanding of the gut-retina axis continues to advance, so too will the possibility for more accessible and effective prevention and therapy of this vision-threatening condition.

6.
Curr Opin Ophthalmol ; 33(4): 332-337, 2022 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-35779058

RESUMEN

PURPOSE OF REVIEW: Currently, the most widely used treatment for endothelial disease is endothelial replacement via endothelial keratoplasty. Increasingly selective techniques have allowed for increased safety and faster visual recovery. However, alternative treatment options that are lower in cost, require less surgical expertise, and rely less on tissue availability are needed. This review discusses established and emerging therapies for endothelial disease without keratoplasty. RECENT FINDINGS: Regenerative therapies that have been successful include Descemet stripping only and Descemet membrane transplants. Rho-kinase inhibitors promote cell proliferation, adhesion, and migration and appear to have a role in these treatments and possibly in the prevention of endothelial disease. Cell-based therapies and the development of an artificial endothelial implant have also demonstrated promising results. SUMMARY: There are numerous emerging treatments for endothelial disease that have proven successful. Advances in our understanding of disease pathogenesis on a cellular level will continue to expand possibilities for therapeutics.


Asunto(s)
Enfermedades de la Córnea , Queratoplastia Endotelial de la Lámina Limitante Posterior , Proliferación Celular , Tratamiento Basado en Trasplante de Células y Tejidos , Enfermedades de la Córnea/patología , Enfermedades de la Córnea/cirugía , Queratoplastia Endotelial de la Lámina Limitante Posterior/métodos , Endotelio Corneal/patología , Humanos
7.
Science ; 379(6633): 677-682, 2023 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-36705538

RESUMEN

N6-methyladenosine (m6A) is the most abundant messenger RNA (mRNA) modification and plays crucial roles in diverse physiological processes. Using a massively parallel assay for m6A (MPm6A), we discover that m6A specificity is globally regulated by suppressors that prevent m6A deposition in unmethylated transcriptome regions. We identify exon junction complexes (EJCs) as m6A suppressors that protect exon junction-proximal RNA within coding sequences from methylation and regulate mRNA stability through m6A suppression. EJC suppression of m6A underlies multiple global characteristics of mRNA m6A specificity, with the local range of EJC protection sufficient to suppress m6A deposition in average-length internal exons but not in long internal and terminal exons. EJC-suppressed methylation sites colocalize with EJC-suppressed splice sites, which suggests that exon architecture broadly determines local mRNA accessibility to regulatory complexes.


Asunto(s)
Exones , Regulación de la Expresión Génica , Empalme del ARN , ARN Mensajero , ARN Mensajero/genética , ARN Mensajero/metabolismo , Humanos , Animales
8.
Science ; 376(6596): 968-973, 2022 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-35511947

RESUMEN

N6-methyladenosine (m6A) is the most abundant internal modification on mammalian messenger RNA. It is installed by a writer complex and can be reversed by erasers such as the fat mass and obesity-associated protein FTO. Despite extensive research, the primary physiological substrates of FTO in mammalian tissues and development remain elusive. Here, we show that FTO mediates m6A demethylation of long-interspersed element-1 (LINE1) RNA in mouse embryonic stem cells (mESCs), regulating LINE1 RNA abundance and the local chromatin state, which in turn modulates the transcription of LINE1-containing genes. FTO-mediated LINE1 RNA m6A demethylation also plays regulatory roles in shaping chromatin state and gene expression during mouse oocyte and embryonic development. Our results suggest broad effects of LINE1 RNA m6A demethylation by FTO in mammals.


Asunto(s)
Adenosina/análogos & derivados , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Cromatina , Regulación del Desarrollo de la Expresión Génica , Elementos de Nucleótido Esparcido Largo , Células Madre Embrionarias de Ratones , Oocitos , ARN Mensajero , Adenosina/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Animales , Cromatina/metabolismo , Desmetilación , Elementos de Nucleótido Esparcido Largo/genética , Ratones , Células Madre Embrionarias de Ratones/metabolismo , Oocitos/crecimiento & desarrollo , ARN Mensajero/genética , ARN Mensajero/metabolismo
9.
Nat Cell Biol ; 24(2): 205-216, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35145225

RESUMEN

METTL16 has recently been identified as an RNA methyltransferase responsible for the deposition of N6-methyladenosine (m6A) in a few transcripts. Whether METTL16 methylates a large set of transcripts, similar to METTL3 and METTL14, remains unclear. Here we show that METTL16 exerts both methyltransferase activity-dependent and -independent functions in gene regulation. In the cell nucleus, METTL16 functions as an m6A writer to deposit m6A into hundreds of its specific messenger RNA targets. In the cytosol, METTL16 promotes translation in an m6A-independent manner. More specifically, METTL16 directly interacts with the eukaryotic initiation factors 3a and -b as well as ribosomal RNA through its Mtase domain, thereby facilitating the assembly of the translation-initiation complex and promoting the translation of over 4,000 mRNA transcripts. Moreover, we demonstrate that METTL16 is critical for the tumorigenesis of hepatocellular carcinoma. Collectively, our studies reveal previously unappreciated dual functions of METTL16 as an m6A writer and a translation-initiation facilitator, which together contribute to its essential function in tumorigenesis.


Asunto(s)
Adenosina/análogos & derivados , Carcinogénesis/metabolismo , Carcinoma Hepatocelular/enzimología , Neoplasias Hepáticas/enzimología , Metiltransferasas/metabolismo , Biosíntesis de Proteínas , Procesamiento Postranscripcional del ARN , ARN Mensajero/metabolismo , Adenosina/metabolismo , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Citosol/enzimología , Factor 3 de Iniciación Eucariótica/genética , Factor 3 de Iniciación Eucariótica/metabolismo , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Metiltransferasas/genética , Ratones Endogámicos NOD , Ratones SCID , ARN Mensajero/genética , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , Transducción de Señal , Carga Tumoral
10.
Cell Res ; 29(2): 91-92, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30631155
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