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A dual role of human tRNA methyltransferase hTrmt13 in regulating translation and transcription [CLIP-seq]

ABSTRACT: Since numerous RNAs and RBPs prevalently localize to active chromatin regions, many RNA binding proteins (RBPs) may be potential transcriptional regulators. RBPs are generally thought to regulate transcription via noncoding RNAs. Here, we describe a distinct, dual mechanism of transcriptional regulation by the previously uncharacterized tRNA-modifying enzyme, hTrmt13. On one hand, hTrmt13 acts in the cytoplasm to catalyze 2'-O-methylation of tRNAs, thus regulating translation in a manner depending on its tRNA-modification activity. On the other hand, nucleus-localized hTrmt13 directly binds DNA as a transcriptional co-activator of key epithelial mesenchymal transition factors, thereby promoting cell migration independent of tRNA-modification activity. These dual functions of hTrmt13 are mutually exclusive, as it can bind either DNA or tRNA through its CHHC zinc finger domain. Finally, we find that hTrmt13 expression is tightly associated with poor prognosis and survival in diverse cancer patients. Our discovery of the noncatalytic roles of an RNA modifying enzyme provides a new perspective for understanding epitranscriptomic regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166274 | GEO | 2021/10/29

REPOSITORIES: GEO

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A dual role of human tRNA methyltransferase hTrmt13 in regulating translation and transcription [RNA-seq]

Project description:Since numerous RNAs and RBPs prevalently localize to active chromatin regions, many RNA binding proteins (RBPs) may be potential transcriptional regulators. RBPs are generally thought to regulate transcription via noncoding RNAs. Here, we describe a distinct, dual mechanism of transcriptional regulation by the previously uncharacterized tRNA-modifying enzyme, hTrmt13. On one hand, hTrmt13 acts in the cytoplasm to catalyze 2'-O-methylation of tRNAs, thus regulating translation in a manner depending on its tRNA-modification activity. On the other hand, nucleus-localized hTrmt13 directly binds DNA as a transcriptional co-activator of key epithelial mesenchymal transition factors, thereby promoting cell migration independent of tRNA-modification activity. These dual functions of hTrmt13 are mutually exclusive, as it can bind either DNA or tRNA through its CHHC zinc finger domain. Finally, we find that hTrmt13 expression is tightly associated with poor prognosis and survival in diverse cancer patients. Our discovery of the noncatalytic roles of an RNA modifying enzyme provides a new perspective for understanding epitranscriptomic regulation.

2021-10-29 | GSE166276 | GEO

A dual role of human tRNA methyltransferase hTrmt13 in regulating translation and transcription [ChIP-seq]

2021-10-29 | GSE166270 | GEO

A highly conserved tRNA modification contributes to C. albicans filamentation and virulence

Project description:tRNA modifications play important roles in maintaining translation accuracy in all domains of life. Disruptions in the tRNA modification machinery, especially of the anticodon stem loop, can be lethal for many bacteria and lead to a broad range of phenotypes in baker’s yeast. Very little is known about the function of tRNA modifications in host-pathogen interactions, where rapidly changing environments and stresses require fast adaptations. We found that two closely related fungal pathogens of humans, the highly pathogenic Candida albicans and its much less pathogenic sister species, Candida dubliniensis, differ in the function of a tRNA-modifying enzyme. This enzyme, Hma1, exhibits speciesspecific effects on the ability of the two fungi to grow in the hypha morphology, which is central to their virulence potential. We show that Hma1 has tRNA-threonylcarbamoyladenosine dehydratase activity, and its deletion alters ribosome occupancy, especially at 37°C—the body temperature of the human host. A C. albicans HMA1 deletion mutant also shows defects in adhesion to and invasion into human epithelial cells and shows reduced virulence in a fungal infection model. This links tRNA modifications to host-induced filamentation and virulence of one of the most important fungal pathogens of humans.

2024-04-04 | GSE199421 | GEO

N7-methylguanosine tRNA modification promotes tumorigenesis and chemoresistance through WNT/β-Catenin pathway in nasopharyngeal carcinoma

Project description:Treatment selections are very limited for patients with advanced nasopharyngeal carcinoma (NPC) experiencing disease progression. Uncovering the potential mechanism underlying NPC progression is crucial for identify novel treatments. Here we show that N7-methylguanosine (m7G) tRNA modification enzyme METTL1 and its partner WDR4 are significantly elevated in NPC and associated with poor prognosis. Loss-of-function and gain-of-function assays demonstrated that METTL1/WDR4 mediated m7G tRNA modification promotes NPC growth and metastasis in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of transcripts with higher percentage of m7G tRNA decoded codons. Moreover, further analysis revealed that METTL1-mediated m7G tRNA modification activates WNT/β-Catenin signaling pathway to promote NPC cell epithelial-mesenchymal transition (EMT) and chemoresistance to cisplatin and docetaxel in vitro and in vivo. Our work uncovers a novel layer of mRNA translation regulation mechanism at codon recognition step mediated by tRNA modification and reveals the critical function of tRNA modification in cancer progression.

2024-03-13 | GSE169589 | GEO

Modifications in the T arm of tRNA globally determine tRNA function and cellular fitness

Project description:Abstract: tRNAs are highly modified in the elbow region and harbor 5-methyluridine at position 54 and pseudouridine at position 55 in the T arm, which are generated by the enzymes TrmA and TruB, respectively. Although all elongator tRNAs contain these modifications across all domains of life, the cellular relevance of these modifications and their corresponding modifying enzymes remains elusive. In addition to modifying every tRNA, Escherichia coli TrmA and TruB have both been shown to fold tRNA independently of its modification activity acting as tRNA chaperones, and strains lacking trmA or truB are outcompeted by wildtype. To identify how TrmA and TruB contribute to cellular fitness, we have systematically assessed the effects of deleting trmA and/or trmB in E. coli. Since tRNA folding is a pre-requisite for tRNA aminoacylation, we determined cellular aminoacylation levels revealing a global decrease in aminoacylation for all tRNAs in ΔtrmA and ΔtruB. Moreover, the absence of 5-methyluridine 54 or pseudouridine 55 alters tRNA modification at other positions: whereas acp3U47 is decreased, thiouridine levels are increased. Understanding the importance of TrmA and TruB for tRNA aminoacylation and modification, we then analyzed how these global tRNA changes in ΔtrmA and ΔtruB strains affect translation. Whereas global protein synthesis is not significantly changed in ΔtrmA and ΔtruB, the abundances of many specific proteins are altered, and transcriptomics experiments suggest that the dysregulation of many proteins is controlled at the translational level. In conclusion, we demonstrate that universally conserved modifications of the tRNA elbow are critical for global tRNA function by enhancing other tRNA modifications, tRNA folding, tRNA aminoacylation and translation of specific genes thereby contributing to cellular fitness.

2023-05-31 | GSE233667 | GEO

tRNA binding to KEOPS human protein complex

Project description:N6-theronylcarbomyl adenosine (t6A) is a universal tRNA posttranscriptional modification that promotes translation fidelity and is therefore required for the fitness of virtually all living cells. Kae1, the t6A modifying enzyme in eukaryotes and archea, resides within the KEOPS complex with three auxiliary subunits of unknown function namely Cgi121, Bud32 and Pcc1. Through biochemical and X-ray crystallographic analyses we show that Cgi121 functions to recruit substrate tRNA to KEOPS via its universal 3’-CCA tail. Incorporation of the Cgi121-tRNA structure into a composite model of KEOPS reveals an extended tRNA contact surface that surprisingly spans all four subunits. Comprehensive mutational and functional analyses validate the relevance of the extended tRNA-binding surface in vivo and in vivo. Together this work provides insight into the t6A catalytic cycle and its regulation through the cooperative action of all four KEOPS subunit through direct contacts with tRNA.

2020-12-11 | PXD018007 | Pride

Profiling tRNA modifications in Mycobacterium tuberculosis

Project description:Diverse chemical modifications fine-tune the function and metabolism of tRNA. Although tRNA modification is universal in all kingdoms of life, profiles of modifications, their functions, and physiological roles have not been elucidated in most organisms including the human pathogen, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. To identify physiologically important modifications, we surveyed the tRNA of Mtb, using tRNA sequencing (tRNA-seq). Reverse transcription-derived error signatures in tRNA-seq predicted the sites and presence of 9 modifications. Several chemical treatments prior to tRNA-seq expanded the number of predictable modifications. Deletion of Mtb genes encoding two modifying enzymes, TruB and MnmA, eliminated their respective tRNA modifications, validating the presence of modified sites in tRNA species.

2023-08-11 | GSE240200 | GEO

Rattus norvegicus

Project description:Fear stress during pregnancy affects placental m6A-modifying enzyme expression and epigenetic modification levels

| PRJNA837736 | ENA

The modification landscape of P. aeruginosa tRNAs

Project description:RNA modifications have a substantial impact on tRNA function. While modifications in the anticodon loop play an important role in translational fidelity, modifications in the tRNA core influence tRNA structural stability. In bacteria, tRNA modifications play important roles in the stress response and expression of virulence factors. While tRNA modifications are well characterized in a few model organisms, our knowledge of tRNA modifications in human pathogens, such as Pseudomonas aeruginosa is lacking. Here we leveraged two orthogonal approaches to build a reference landscape of tRNA modifications in E. coli, which we used to identify tRNA modifications in P. aeruginosa. We determined conservation for many modifications between the two organisms. We also identified potential sites of tRNA modification in P. aeruginosa tRNA that are not present in E. coli. One of these sites is found at the same positions as acacp3U, a modification previously identified in Vibrio cholerae. Identifying which modifications are present on different tRNAs will uncover the pathways impacted by the different tRNA modifying enzymes, some of which may play roles in determining virulence and pathogenicity.

2024-04-03 | GSE236676 | GEO

Transcriptome analysis upon Sin3A or Sam-S knockdown or both in Drosophila cultured S2 cells

Project description:The SIN3 histone modifying complex regulates the expression of multiple methionine catabolic genes including SAM synthetase (Sam-S) as well as the level of S-adenosyl-methionine (SAM). To further investigate the relationship between methionine catabolism and epigenetic regulation by SIN3, we identified genes controlled by SIN3 and SAM-S. As a global transcriptional regulator, SIN3 impacted a wide range of genes. Independently, SAM-S affected a narrow range of genes. Additional genes, however, were influenced in dual knockdown cells. At some genes, SIN3 and SAM-S act independently, for others, redundantly and for a third set, in opposition. Together, the results obtained in the study of SIN3, a cofactor associated with histone modification, and SAM-S, a metabolic enzyme, uncover a complex relationship on regulating transcription.

2019-11-26 | GSE129145 | GEO

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