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1.
Annu Rev Immunol ; 35: 177-198, 2017 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-28125358

RESUMEN

The discovery of long noncoding RNAs (lncRNA) has provided a new perspective on gene regulation in diverse biological contexts. lncRNAs are remarkably versatile molecules that interact with RNA, DNA, or proteins to promote or restrain the expression of protein-coding genes. Activation of immune cells is associated with dynamic changes in expression of genes, the products of which combat infectious microorganisms, initiate repair, and resolve inflammatory responses in cells and tissues. Recent evidence indicates that lncRNAs play important roles in directing the development of diverse immune cells and controlling the dynamic transcriptional programs that are a hallmark of immune cell activation. The importance of these molecules is underscored by their newly recognized roles in inflammatory diseases. In this review, we discuss the contribution of lncRNAs in the development and activation of immune cells and their roles in immune-related diseases. We also discuss challenges faced in identifying biological functions for this large and complex class of genes.


Asunto(s)
Enfermedades del Sistema Inmune/genética , Inmunidad/genética , ARN Largo no Codificante/inmunología , Animales , Regulación de la Expresión Génica , Humanos
2.
Cell ; 184(1): 207-225.e24, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33333019

RESUMEN

Regulation of biological processes typically incorporates mechanisms that initiate and terminate the process and, where understood, these mechanisms often involve feedback control. Regulation of transcription is a fundamental cellular process where the mechanisms involved in initiation have been studied extensively, but those involved in arresting the process are poorly understood. Modeling of the potential roles of RNA in transcriptional control suggested a non-equilibrium feedback control mechanism where low levels of RNA promote condensates formed by electrostatic interactions whereas relatively high levels promote dissolution of these condensates. Evidence from in vitro and in vivo experiments support a model where RNAs produced during early steps in transcription initiation stimulate condensate formation, whereas the burst of RNAs produced during elongation stimulate condensate dissolution. We propose that transcriptional regulation incorporates a feedback mechanism whereby transcribed RNAs initially stimulate but then ultimately arrest the process.


Asunto(s)
Retroalimentación Fisiológica , ARN/genética , Transcripción Genética , Animales , Complejo Mediador/metabolismo , Ratones , Modelos Biológicos , Células Madre Embrionarias de Ratones/metabolismo , ARN/biosíntesis , Electricidad Estática
3.
Cell ; 184(25): 6157-6173.e24, 2021 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-34856126

RESUMEN

Chromosome loops shift dynamically during development, homeostasis, and disease. CCCTC-binding factor (CTCF) is known to anchor loops and construct 3D genomes, but how anchor sites are selected is not yet understood. Here, we unveil Jpx RNA as a determinant of anchor selectivity. Jpx RNA targets thousands of genomic sites, preferentially binding promoters of active genes. Depleting Jpx RNA causes ectopic CTCF binding, massive shifts in chromosome looping, and downregulation of >700 Jpx target genes. Without Jpx, thousands of lost loops are replaced by de novo loops anchored by ectopic CTCF sites. Although Jpx controls CTCF binding on a genome-wide basis, it acts selectively at the subset of developmentally sensitive CTCF sites. Specifically, Jpx targets low-affinity CTCF motifs and displaces CTCF protein through competitive inhibition. We conclude that Jpx acts as a CTCF release factor and shapes the 3D genome by regulating anchor site usage.


Asunto(s)
Factor de Unión a CCCTC/metabolismo , Cromosomas/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Sitios de Unión , Línea Celular , Células Madre Embrionarias , Ratones , Unión Proteica
4.
Annu Rev Cell Dev Biol ; 38: 263-289, 2022 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-35609906

RESUMEN

Covalently closed, single-stranded circular RNAs can be produced from viral RNA genomes as well as from the processing of cellular housekeeping noncoding RNAs and precursor messenger RNAs. Recent transcriptomic studies have surprisingly uncovered that many protein-coding genes can be subjected to backsplicing, leading to widespread expression of a specific type of circular RNAs (circRNAs) in eukaryotic cells. Here, we discuss experimental strategies used to discover and characterize diverse circRNAs at both the genome and individual gene scales. We further highlight the current understanding of how circRNAs are generated and how the mature transcripts function. Some circRNAs act as noncoding RNAs to impact gene regulation by serving as decoys or competitors for microRNAs and proteins. Others form extensive networks of ribonucleoprotein complexes or encode functional peptides that are translated in response to certain cellular stresses. Overall, circRNAs have emerged as an important class of RNAmolecules in gene expression regulation that impact many physiological processes, including early development, immune responses, neurogenesis, and tumorigenesis.


Asunto(s)
MicroARNs , ARN Circular , Regulación de la Expresión Génica/genética , MicroARNs/genética , MicroARNs/metabolismo , ARN/genética , ARN/metabolismo , ARN Circular/genética , ARN no Traducido , ARN Viral , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo
5.
Annu Rev Biochem ; 89: 255-282, 2020 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-32259458

RESUMEN

Facultative heterochromatin (fHC) concerns the developmentally regulated heterochromatinization of different regions of the genome and, in the case of the mammalian X chromosome and imprinted loci, of only one allele of a homologous pair. The formation of fHC participates in the timely repression of genes, by resisting strong trans activators. In this review, we discuss the molecular mechanisms underlying the establishment and maintenance of fHC in mammals using a mouse model. We focus on X-chromosome inactivation (XCI) as a paradigm for fHC but also relate it to genomic imprinting and homeobox (Hox) gene cluster repression. A vital role for noncoding transcription and/or transcripts emerges as the general principle of triggering XCI and canonical imprinting. However, other types of fHC are established through an unknown mechanism, independent of noncoding transcription (Hox clusters and noncanonical imprinting). We also extensively discuss polycomb-group repressive complexes (PRCs), which frequently play a vital role in fHC maintenance.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Impresión Genómica , Heterocromatina/metabolismo , Proteínas del Grupo Polycomb/genética , Inactivación del Cromosoma X , Cromosoma X/metabolismo , Animales , Ensamble y Desensamble de Cromatina , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Embrión de Mamíferos , Femenino , Silenciador del Gen , Heterocromatina/química , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Oocitos/citología , Oocitos/crecimiento & desarrollo , Oocitos/metabolismo , Proteínas del Grupo Polycomb/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Espermatozoides/citología , Espermatozoides/crecimiento & desarrollo , Espermatozoides/metabolismo , Cromosoma X/química
6.
Annu Rev Biochem ; 89: 283-308, 2020 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-32569523

RESUMEN

We have known for decades that long noncoding RNAs (lncRNAs) can play essential functions across most forms of life. The maintenance of chromosome length requires an lncRNA (e.g., hTERC) and two lncRNAs in the ribosome that are required for protein synthesis. Thus, lncRNAs can represent powerful RNA machines. More recently, it has become clear that mammalian genomes encode thousands more lncRNAs. Thus, we raise the question: Which, if any, of these lncRNAs could also represent RNA-based machines? Here we synthesize studies that are beginning to address this question by investigating fundamental properties of lncRNA genes, revealing new insights into the RNA structure-function relationship, determining cis- and trans-acting lncRNAs in vivo, and generating new developments in high-throughput screening used to identify functional lncRNAs. Overall, these findings provide a context toward understanding the molecular grammar underlying lncRNA biology.


Asunto(s)
Genoma , Biosíntesis de Proteínas , ARN Largo no Codificante/genética , ARN Mensajero/genética , ARN/genética , Telomerasa/genética , Animales , Núcleo Celular/genética , Núcleo Celular/metabolismo , Células Eucariotas/citología , Células Eucariotas/metabolismo , Humanos , Conformación de Ácido Nucleico , Regiones Promotoras Genéticas , ARN/metabolismo , ARN Largo no Codificante/química , ARN Largo no Codificante/metabolismo , ARN Mensajero/química , ARN Mensajero/metabolismo , Relación Estructura-Actividad , Telomerasa/metabolismo , Homeostasis del Telómero , Transcripción Genética
7.
Cell ; 181(3): 621-636.e22, 2020 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-32259487

RESUMEN

Long noncoding RNAs (lncRNAs) evolve more rapidly than mRNAs. Whether conserved lncRNAs undergo conserved processing, localization, and function remains unexplored. We report differing subcellular localization of lncRNAs in human and mouse embryonic stem cells (ESCs). A significantly higher fraction of lncRNAs is localized in the cytoplasm of hESCs than in mESCs. This turns out to be important for hESC pluripotency. FAST is a positionally conserved lncRNA but is not conserved in its processing and localization. In hESCs, cytoplasm-localized hFAST binds to the WD40 domain of the E3 ubiquitin ligase ß-TrCP and blocks its interaction with phosphorylated ß-catenin to prevent degradation, leading to activated WNT signaling, required for pluripotency. In contrast, mFast is nuclear retained in mESCs, and its processing is suppressed by the splicing factor PPIE, which is highly expressed in mESCs but not hESCs. These findings reveal that lncRNA processing and localization are previously under-appreciated contributors to the rapid evolution of function.


Asunto(s)
Espacio Intracelular/genética , ARN Largo no Codificante/metabolismo , Células Madre/metabolismo , Animales , Diferenciación Celular/genética , Línea Celular , Células Cultivadas , Células Madre Embrionarias/metabolismo , Células Madre Embrionarias Humanas/metabolismo , Humanos , Ratones , Células Madre Embrionarias de Ratones/metabolismo , Empalme del ARN/genética , ARN Largo no Codificante/genética , ARN Mensajero/metabolismo , Transducción de Señal/genética , Células Madre/patología
8.
Cell ; 172(3): 393-407, 2018 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-29373828

RESUMEN

Over the last decade, it has been increasingly demonstrated that the genomes of many species are pervasively transcribed, resulting in the production of numerous long noncoding RNAs (lncRNAs). At the same time, it is now appreciated that many types of DNA regulatory elements, such as enhancers and promoters, regularly initiate bi-directional transcription. Thus, discerning functional noncoding transcripts from a vast transcriptome is a paramount priority, and challenge, for the lncRNA field. In this review, we aim to provide a conceptual and experimental framework for classifying and elucidating lncRNA function. We categorize lncRNA loci into those that regulate gene expression in cis versus those that perform functions in trans and propose an experimental approach to dissect lncRNA activity based on these classifications. These strategies to further understand lncRNAs promise to reveal new and unanticipated biology with great potential to advance our understanding of normal physiology and disease.


Asunto(s)
ARN Largo no Codificante/genética , Animales , Humanos , ARN Largo no Codificante/clasificación , ARN Largo no Codificante/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Transcripción Genética
9.
Cell ; 175(7): 1887-1901.e18, 2018 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-30550787

RESUMEN

In early mammalian embryos, it remains unclear how the first cell fate bias is initially triggered and amplified toward cell fate segregation. Here, we report that a long noncoding RNA, LincGET, is transiently and asymmetrically expressed in the nucleus of two- to four-cell mouse embryos. Overexpression of LincGET in one of the two-cell blastomeres biases its progeny predominantly toward the inner cell mass (ICM) fate. Mechanistically, LincGET physically binds to CARM1 and promotes the nuclear localization of CARM1, which can further increase the level of H3 methylation at Arginine 26 (H3R26me), activate ICM-specific gene expression, upregulate transposons, and increase global chromatin accessibility. Simultaneous overexpression of LincGET and depletion of Carm1 no longer biased embryonic fate, indicating that the effect of LincGET in directing ICM lineage depends on CARM1. Thus, our data identify LincGET as one of the earliest known lineage regulators to bias cell fate in mammalian 2-cell embryos.


Asunto(s)
Blastocisto/metabolismo , Blastómeros/metabolismo , Linaje de la Célula/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , ARN Largo no Codificante/biosíntesis , Animales , Blastocisto/citología , Blastómeros/citología , Femenino , Histonas/metabolismo , Metilación , Ratones , Ratones Endogámicos ICR , Proteína-Arginina N-Metiltransferasas/biosíntesis , Proteína-Arginina N-Metiltransferasas/genética , ARN Largo no Codificante/genética
10.
Cell ; 174(2): 350-362.e17, 2018 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-29887379

RESUMEN

Noncoding RNAs (ncRNAs) play increasingly appreciated gene-regulatory roles. Here, we describe a regulatory network centered on four ncRNAs-a long ncRNA, a circular RNA, and two microRNAs-using gene editing in mice to probe the molecular consequences of disrupting key components of this network. The long ncRNA Cyrano uses an extensively paired site to miR-7 to trigger destruction of this microRNA. Cyrano-directed miR-7 degradation is much more effective than previously described examples of target-directed microRNA degradation, which come primarily from studies of artificial and viral RNAs. By reducing miR-7 levels, Cyrano prevents repression of miR-7-targeted mRNAs and enables accumulation of Cdr1as, a circular RNA known to regulate neuronal activity. Without Cyrano, excess miR-7 causes cytoplasmic destruction of Cdr1as in neurons, in part through enhanced slicing of Cdr1as by a second miRNA, miR-671. Thus, several types of ncRNAs can collaborate to establish a sophisticated regulatory network.


Asunto(s)
Encéfalo/metabolismo , Redes Reguladoras de Genes , ARN no Traducido/metabolismo , Animales , Citoplasma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , MicroARNs/metabolismo , Neuronas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo
11.
Cell ; 169(3): 523-537.e15, 2017 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-28431250

RESUMEN

The distribution of sense and antisense strand DNA mutations on transcribed duplex DNA contributes to the development of immune and neural systems along with the progression of cancer. Because developmentally matured B cells undergo biologically programmed strand-specific DNA mutagenesis at focal DNA/RNA hybrid structures, they make a convenient system to investigate strand-specific mutagenesis mechanisms. We demonstrate that the sense and antisense strand DNA mutagenesis at the immunoglobulin heavy chain locus and some other regions of the B cell genome depends upon localized RNA processing protein complex formation in the nucleus. Both the physical proximity and coupled activities of RNA helicase Mtr4 (and senataxin) with the noncoding RNA processing function of RNA exosome determine the strand-specific distribution of DNA mutations. Our study suggests that strand-specific DNA mutagenesis-associated mechanisms will play major roles in other undiscovered aspects of organismic development.


Asunto(s)
Linfocitos B/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma/metabolismo , Mutación , Proteínas Nucleares/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Núcleo Celular/metabolismo , ADN Helicasas/metabolismo , Exorribonucleasas/genética , Inestabilidad Genómica , Cadenas Pesadas de Inmunoglobulina/genética , Ratones , Enzimas Multifuncionales , Proteínas Nucleares/genética , ARN Helicasas , Procesamiento Postranscripcional del ARN , Proteínas de Unión al ARN/genética
12.
Mol Cell ; 84(10): 1870-1885.e9, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38759625

RESUMEN

How Polycomb repressive complex 2 (PRC2) is regulated by RNA remains an unsolved problem. Although PRC2 binds G-tracts with the potential to form RNA G-quadruplexes (rG4s), whether rG4s fold extensively in vivo and whether PRC2 binds folded or unfolded rG4 are unknown. Using the X-inactivation model in mouse embryonic stem cells, here we identify multiple folded rG4s in Xist RNA and demonstrate that PRC2 preferentially binds folded rG4s. High-affinity rG4 binding inhibits PRC2's histone methyltransferase activity, and stabilizing rG4 in vivo antagonizes H3 at lysine 27 (H3K27me3) enrichment on the inactive X chromosome. Surprisingly, mutagenizing the rG4 does not affect PRC2 recruitment but promotes its release and catalytic activation on chromatin. H3K27me3 marks are misplaced, however, and gene silencing is compromised. Xist-PRC2 complexes become entrapped in the S1 chromosome compartment, precluding the required translocation into the S2 compartment. Thus, Xist rG4 folding controls PRC2 activity, H3K27me3 enrichment, and the stepwise regulation of chromosome-wide gene silencing.


Asunto(s)
G-Cuádruplex , Histonas , Complejo Represivo Polycomb 2 , ARN Largo no Codificante , Inactivación del Cromosoma X , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ratones , Complejo Represivo Polycomb 2/metabolismo , Complejo Represivo Polycomb 2/genética , Histonas/metabolismo , Histonas/genética , Células Madre Embrionarias de Ratones/metabolismo , Cromatina/metabolismo , Cromatina/genética , Cromosoma X/genética , Cromosoma X/metabolismo , Silenciador del Gen , Pliegue del ARN , Unión Proteica
13.
Genes Dev ; 38(17-20): 915-930, 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39362776

RESUMEN

Long noncoding (lnc)RNAs emerge as regulators of genome stability. The nuclear-enriched abundant transcript 1 (NEAT1) is overexpressed in many tumors and is responsive to genotoxic stress. However, the mechanism that links NEAT1 to DNA damage response (DDR) is unclear. Here, we investigate the expression, modification, localization, and structure of NEAT1 in response to DNA double-strand breaks (DSBs). DNA damage increases the levels and N6-methyladenosine (m6A) marks on NEAT1, which promotes alterations in NEAT1 structure, accumulation of hypermethylated NEAT1 at promoter-associated DSBs, and DSB signaling. The depletion of NEAT1 impairs DSB focus formation and elevates DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves the release of the chromodomain helicase DNA binding protein 4 (CHD4) from NEAT1 to fine-tune histone acetylation at DSBs. Our data suggest a direct role for NEAT1 in DDR.


Asunto(s)
Adenosina , Roturas del ADN de Doble Cadena , Inestabilidad Genómica , Metiltransferasas , ARN Largo no Codificante , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Inestabilidad Genómica/genética , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Metiltransferasas/metabolismo , Metiltransferasas/genética , Metilación , Daño del ADN/genética , ADN Helicasas/metabolismo , ADN Helicasas/genética , Histonas/metabolismo , Histonas/genética , Regulación de la Expresión Génica
14.
Mol Cell ; 83(24): 4479-4493.e6, 2023 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-38096826

RESUMEN

4.5SH RNA is a highly abundant, small rodent-specific noncoding RNA that localizes to nuclear speckles enriched in pre-mRNA-splicing regulators. To investigate the physiological functions of 4.5SH RNA, we have created mutant mice that lack the expression of 4.5SH RNA. The mutant mice exhibited embryonic lethality, suggesting that 4.5SH RNA is an essential species-specific noncoding RNA in mice. RNA-sequencing analyses revealed that 4.5SH RNA protects the transcriptome from abnormal exonizations of the antisense insertions of the retrotransposon SINE B1 (asB1), which would otherwise introduce deleterious premature stop codons or frameshift mutations. Mechanistically, 4.5SH RNA base pairs with complementary asB1-containing exons via the target recognition region and recruits effector proteins including Hnrnpm via its 5' stem loop region. The modular organization of 4.5SH RNA allows us to engineer a programmable splicing regulator to induce the skipping of target exons of interest. Our results also suggest the general existence of splicing regulatory noncoding RNAs.


Asunto(s)
Empalme del ARN , ARN Pequeño no Traducido , Ratones , Animales , Empalme del ARN/genética , Exones/genética , Retroelementos/genética , Codón sin Sentido , Empalme Alternativo
15.
Genes Dev ; 37(3-4): 103-118, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36746605

RESUMEN

RNA-directed DNA methylation in plants is guided by 24-nt siRNAs generated in parallel with 23-nt RNAs of unknown function. We show that 23-nt RNAs function as passenger strands during 24-nt siRNA incorporation into AGO4. The 23-nt RNAs are then sliced into 11- and 12-nt fragments, with 12-nt fragments remaining associated with AGO4. Slicing recapitulated with recombinant AGO4 and synthetic RNAs reveals that siRNAs of 21-24 nt, with any 5'-terminal nucleotide, can guide slicing, with sliced RNAs then retained by AGO4. In vivo, RdDM target locus RNAs that copurify with AGO4 also display a sequence signature of slicing. Comparing plants expressing slicing-competent versus slicing-defective AGO4 shows that slicing elevates cytosine methylation levels at virtually all RdDM loci. We propose that siRNA passenger strand elimination and AGO4 tethering to sliced target RNAs are distinct modes by which AGO4 slicing enhances RNA-directed DNA methylation.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Metilación de ADN , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Silenciador del Gen , ARN de Planta/genética , ARN de Planta/metabolismo , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo
16.
Genes Dev ; 37(3-4): 69-71, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36754778

RESUMEN

Throughout the eukaryotic kingdoms, small RNAs direct chromatin modification. ARGONAUTE proteins sit at the nexus of this process, linking the small RNA information to the programming of chromatin. ARGONAUTE proteins physically incorporate the small RNAs as guides to target specific regions of the genome. In this issue of Genes & Development, Wang and colleagues (pp. 103-118) add substantial new detail to the processes of ARGONAUTE RNA loading, preference, cleavage, and retention, which together accomplish RNA-directed chromatin modification. They show that after catalytic cleavage by the plant ARGONAUTE protein AGO4, the cleaved fragment remains bound. This happens during two distinct RNA cleavage reactions performed by AGO4: first for a passenger RNA strand of the siRNA duplex, and second for a nascent transcript at the target DNA locus. Cleaved fragment retention of the nascent transcript explains how the protein complex accumulates to high levels at the target locus, amplifying chromatin modification.


Asunto(s)
Proteínas Argonautas , Cromatina , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , ARN Interferente Pequeño/metabolismo , ARN Bicatenario
17.
Mol Cell ; 82(19): 3729-3744.e10, 2022 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-36167073

RESUMEN

Arthropod-borne viruses, including the alphavirus chikungunya virus (CHIKV), cause acute disease in millions of people and utilize potent mechanisms to antagonize and circumvent innate immune pathways including the type I interferon (IFN) pathway. In response, hosts have evolved antiviral counterdefense strategies that remain incompletely understood. Recent studies have found that long noncoding RNAs (lncRNAs) regulate classical innate immune pathways; how lncRNAs contribute to additional antiviral counterdefenses remains unclear. Using high-throughput genetic screening, we identified a cytoplasmic antiviral lncRNA that we named antiviral lncRNA prohibiting human alphaviruses (ALPHA), which is transcriptionally induced by alphaviruses and functions independently of IFN to inhibit the replication of CHIKV and its closest relative, O'nyong'nyong virus (ONNV), but not other viruses. Furthermore, we showed that ALPHA interacts with CHIKV genomic RNA and restrains viral RNA replication. Together, our findings reveal that ALPHA and potentially other lncRNAs can mediate non-canonical antiviral immune responses against specific viruses.


Asunto(s)
Virus Chikungunya , Interferón Tipo I , ARN Largo no Codificante , Antivirales/farmacología , Virus Chikungunya/genética , Humanos , Inmunidad Innata/genética , Interferón Tipo I/genética , ARN Largo no Codificante/genética , ARN Viral/genética , Replicación Viral/genética
18.
Mol Cell ; 82(9): 1708-1723.e10, 2022 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-35320755

RESUMEN

7SK is a conserved noncoding RNA that regulates transcription by sequestering the transcription factor P-TEFb. 7SK function entails complex changes in RNA structure, but characterizing RNA dynamics in cells remains an unsolved challenge. We developed a single-molecule chemical probing strategy, DANCE-MaP (deconvolution and annotation of ribonucleic conformational ensembles), that defines per-nucleotide reactivity, direct base pairing interactions, tertiary interactions, and thermodynamic populations for each state in RNA structural ensembles from a single experiment. DANCE-MaP reveals that 7SK RNA encodes a large-scale structural switch that couples dissolution of the P-TEFb binding site to structural remodeling at distal release factor binding sites. The 7SK structural equilibrium shifts in response to cell growth and stress and can be targeted to modulate expression of P-TEFbresponsive genes. Our study reveals that RNA structural dynamics underlie 7SK function as an integrator of diverse cellular signals to control transcription and establishes the power of DANCE-MaP to define RNA dynamics in cells.


Asunto(s)
Factor B de Elongación Transcripcional Positiva , Proteínas de Unión al ARN , Sitios de Unión/genética , Células HeLa , Humanos , Factor B de Elongación Transcripcional Positiva/genética , ARN Nuclear Pequeño/genética , ARN no Traducido , Proteínas de Unión al ARN/genética
19.
Mol Cell ; 82(7): 1297-1312.e8, 2022 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-35219381

RESUMEN

Synthetic lethality through combinatorial targeting DNA damage response (DDR) pathways provides exciting anticancer therapeutic benefit. Currently, the long noncoding RNAs (lncRNAs) have been implicated in tumor drug resistance; however, their potential significance in DDR is still largely unknown. Here, we report that a human lncRNA, CTD-2256P15.2, encodes a micropeptide, named PAR-amplifying and CtIP-maintaining micropeptide (PACMP), with a dual function to maintain CtIP abundance and promote poly(ADP-ribosyl)ation. PACMP not only prevents CtIP from ubiquitination through inhibiting the CtIP-KLHL15 association but also directly binds DNA damage-induced poly(ADP-ribose) chains to enhance PARP1-dependent poly(ADP-ribosyl)ation. Targeting PACMP alone inhibits tumor growth by causing a synthetic lethal interaction between CtIP and PARP inhibitions and confers sensitivity to PARP/ATR/CDK4/6 inhibitors, ionizing radiation, epirubicin, and camptothecin. Our findings reveal that a lncRNA-derived micropeptide regulates cancer progression and drug resistance by modulating DDR, whose inhibition could be employed to augment the existing anticancer therapeutic strategies.


Asunto(s)
Endodesoxirribonucleasas , Neoplasias , Péptidos , Poli ADP Ribosilación , ARN Largo no Codificante , Reparación del ADN , Endodesoxirribonucleasas/metabolismo , Humanos , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Péptidos/farmacología , Poli Adenosina Difosfato Ribosa/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo
20.
Immunity ; 53(6): 1168-1181.e7, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33326766

RESUMEN

Viruses have evolved multiple strategies to evade elimination by the immune system. Here we examined the contribution of host long noncoding RNAs (lncRNAs) in viral immune evasion. By functional screening of lncRNAs whose expression decreased upon viral infection of macrophages, we identified a lncRNA (lncRNA-GM, Gene Symbol: AK189470.1) that promoted type I interferon (IFN-I) production and inhibited viral replication. Deficiency of lncRNA-GM in mice increased susceptibility to viral infection and impaired IFN-I production. Mechanistically, lncRNA-GM bound to glutathione S-transferase M1 (GSTM1) and blocked GSTM1 interaction with the kinase TBK1, reducing GSTM1-mediated S-glutathionylation of TBK1. Decreased S-glutathionylation enhanced TBK1 activity and downstream production of antiviral mediators. Viral infection reprogrammed intracellular glutathione metabolism and furthermore, an oxidized glutathione mimetic could inhibit TBK1 activity and promote viral replication. Our findings reveal regulation of TBK1 by S-glutathionylation and provide insight into the viral mediated metabolic changes that impact innate immunity and viral evasion.


Asunto(s)
Glutatión/metabolismo , Evasión Inmune , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Glutatión Transferasa/metabolismo , Humanos , Inmunidad Innata , Factor 3 Regulador del Interferón/metabolismo , Interferón Tipo I/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , ARN Largo no Codificante/genética , Transducción de Señal , Virosis/genética , Virosis/inmunología , Virosis/metabolismo , Replicación Viral
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