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1.
Cell ; 173(5): 1204-1216.e26, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29628141

RESUMO

Pseudouridylation (Ψ) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of Ψ remains poorly understood. Here, we show that a Ψ-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the Ψ "writer" PUS7 modifies and activates a novel network of tRNA-derived small fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF-mediated translation regulation, leading to increased protein biosynthesis and defective germ layer specification. Remarkably, dysregulation of this posttranscriptional regulatory circuitry impairs hematopoietic stem cell commitment and is common to aggressive subtypes of human myelodysplastic syndromes. Our findings unveil a critical function of Ψ in directing translation control in stem cells with important implications for development and disease.


Assuntos
Transferases Intramoleculares/metabolismo , Biossíntese de Proteínas , Pseudouridina/metabolismo , RNA de Transferência/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular , Diferenciação Celular , Fatores de Iniciação em Eucariotos/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Transferases Intramoleculares/antagonistas & inibidores , Transferases Intramoleculares/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Síndromes Mielodisplásicas/patologia , Conformação de Ácido Nucleico , Fosfoproteínas/metabolismo , Proteína I de Ligação a Poli(A)/antagonistas & inibidores , Proteína I de Ligação a Poli(A)/genética , Proteína I de Ligação a Poli(A)/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Nicho de Células-Tronco
2.
EMBO J ; 40(2): e107097, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33346912

RESUMO

Transfer RNAs (tRNAs) are central adaptors that decode genetic information during translation and have been long considered static cellular components. However, whether dynamic changes in tRNAs and tRNA-derived fragments actively contribute to gene regulation remains debated. In this issue, Huh et al (2020) highlight tyrosine tRNAGUA fragmentation at the nexus of an evolutionarily conserved adaptive codon-based stress response that fine-tunes translation to restrain growth in human cells.


Assuntos
Biossíntese de Proteínas , RNA de Transferência , Ciclo Celular , Códon/genética , Humanos , Biossíntese de Proteínas/genética , RNA de Transferência/genética , RNA de Transferência/metabolismo , Tirosina
3.
PLoS Biol ; 17(12): e3000559, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31877125

RESUMO

The global rise in obesity and steady decline in sperm quality are two alarming trends that have emerged during recent decades. In parallel, evidence from model organisms shows that paternal diet can affect offspring metabolic health in a process involving sperm tRNA-derived small RNA (tsRNA). Here, we report that human sperm are acutely sensitive to nutrient flux, both in terms of sperm motility and changes in sperm tsRNA. Over the course of a 2-week diet intervention, in which we first introduced a healthy diet followed by a diet rich in sugar, sperm motility increased and stabilized at high levels. Small RNA-seq on repeatedly sampled sperm from the same individuals revealed that tsRNAs were up-regulated by eating a high-sugar diet for just 1 week. Unsupervised clustering identified two independent pathways for the biogenesis of these tsRNAs: one involving a novel class of fragments with specific cleavage in the T-loop of mature nuclear tRNAs and the other exclusively involving mitochondrial tsRNAs. Mitochondrial involvement was further supported by a similar up-regulation of mitochondrial rRNA-derived small RNA (rsRNA). Notably, the changes in sugar-sensitive tsRNA were positively associated with simultaneous changes in sperm motility and negatively associated with obesity in an independent clinical cohort. This rapid response to a dietary intervention on tsRNA in human sperm is attuned with the paternal intergenerational metabolic responses found in model organisms. More importantly, our findings suggest shared diet-sensitive mechanisms between sperm motility and the biogenesis of tsRNA, which provide novel insights about the interplay between nutrition and male reproductive health.


Assuntos
Dieta/métodos , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Adulto , Humanos , Masculino , Obesidade/metabolismo , RNA/efeitos dos fármacos , RNA/genética , RNA de Transferência/efeitos dos fármacos , RNA de Transferência/genética , Motilidade dos Espermatozoides/fisiologia , Espermatozoides/metabolismo , Espermatozoides/fisiologia
4.
RNA Biol ; 17(8): 1214-1222, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32116113

RESUMO

ABTRACT tRNA-derived fragments or tRFs were long considered merely degradation intermediates of full-length tRNAs; however, emerging research is highlighting unanticipated new and highly distinct functions in epigenetic control, metabolism, immune activity and stem cell fate commitment. Importantly, recent studies suggest that RNA epitranscriptomic modifications may provide an additional regulatory layer that dynamically directs tRF activity in stem and cancer cells. In this review, we explore current work illustrating unanticipated roles of tRFs in mammalian stem cells with a focus on the impact of post-transcriptional RNA modifications for the biogenesis and function of this growing class of small noncoding RNAs.


Assuntos
Regulação da Expressão Gênica , Pequeno RNA não Traduzido/genética , RNA de Transferência/genética , Animais , Diferenciação Celular/genética , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Epigênese Genética , Células Germinativas , Hematopoese , Humanos , Imunidade , Padrões de Herança , Especificidade de Órgãos/genética , Processamento Pós-Transcricional do RNA
5.
Cell Rep ; 42(2): 112099, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36763502

RESUMO

MLL-rearrangements (MLL-r) are recurrent genetic events in acute myeloid leukemia (AML) and frequently associate with poor prognosis. In infants, MLL-r can be sufficient to drive transformation. However, despite the prenatal origin of MLL-r in these patients, congenital leukemia is very rare with transformation usually occurring postnatally. The influence of prenatal signals on leukemogenesis, such as those mediated by the fetal-specific protein LIN28B, remains controversial. Here, using a dual-transgenic mouse model that co-expresses MLL-ENL and LIN28B, we investigate the impact of LIN28B on AML. LIN28B impedes the progression of MLL-r AML through compromised leukemia-initiating cell activity and suppression of MYB signaling. Mechanistically, LIN28B directly binds to MYBBP1A mRNA, resulting in elevated protein levels of this MYB co-repressor. Functionally, overexpression of MYBBP1A phenocopies the tumor-suppressor effects of LIN28B, while its perturbation omits it. Thereby, we propose that developmentally restricted expression of LIN28B provides a layer of protection against MYB-dependent AML.


Assuntos
Leucemia Mieloide Aguda , Proteína de Leucina Linfoide-Mieloide , Humanos , Camundongos , Animais , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Rearranjo Gênico , Camundongos Transgênicos , Transformação Celular Neoplásica/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Ligação a RNA/genética
6.
Elife ; 112022 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-35758650

RESUMO

Cells encountering stressful situations activate the integrated stress response (ISR) pathway to limit protein synthesis and redirect translation to better cope. The ISR has also been implicated in cancers, but redundancies in the stress-sensing kinases that trigger the ISR have posed hurdles to dissecting physiological relevance. To overcome this challenge, we targeted the regulatory node of these kinases, namely, the S51 phosphorylation site of eukaryotic translation initiation factor eIF2α and genetically replaced eIF2α with eIF2α-S51A in mouse squamous cell carcinoma (SCC) stem cells of skin. While inconsequential under normal growth conditions, the vulnerability of this ISR-null state was unveiled when SCC stem cells experienced proteotoxic stress. Seeking mechanistic insights into the protective roles of the ISR, we combined ribosome profiling and functional approaches to identify and probe the functional importance of translational differences between ISR-competent and ISR-null SCC stem cells when exposed to proteotoxic stress. In doing so, we learned that the ISR redirects translation to centrosomal proteins that orchestrate the microtubule dynamics needed to efficiently concentrate unfolded proteins at the microtubule-organizing center so that they can be cleared by the perinuclear degradation machinery. Thus, rather than merely maintaining survival during proteotoxic stress, the ISR also functions in promoting cellular recovery once the stress has subsided. Remarkably, this molecular program is unique to transformed skin stem cells, hence exposing a vulnerability in cancer that could be exploited therapeutically.


Assuntos
Centro Organizador dos Microtúbulos , Estresse Fisiológico , Animais , Fator de Iniciação 2 em Eucariotos/metabolismo , Camundongos , Centro Organizador dos Microtúbulos/metabolismo , Fosforilação , Proteínas/metabolismo
7.
Nat Cell Biol ; 24(3): 299-306, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35292784

RESUMO

Transfer RNA-derived fragments (tRFs) are emerging small noncoding RNAs that, although commonly altered in cancer, have poorly defined roles in tumorigenesis1. Here we show that pseudouridylation (Ψ) of a stem cell-enriched tRF subtype2, mini tRFs containing a 5' terminal oligoguanine (mTOG), selectively inhibits aberrant protein synthesis programmes, thereby promoting engraftment and differentiation of haematopoietic stem and progenitor cells (HSPCs) in patients with myelodysplastic syndrome (MDS). Building on evidence that mTOG-Ψ targets polyadenylate-binding protein cytoplasmic 1 (PABPC1), we employed isotope exchange proteomics to reveal critical interactions between mTOG and functional RNA-recognition motif (RRM) domains of PABPC1. Mechanistically, this hinders the recruitment of translational co-activator PABPC1-interacting protein 1 (PAIP1)3 and strongly represses the translation of transcripts sharing pyrimidine-enriched sequences (PES) at the 5' untranslated region (UTR), including 5' terminal oligopyrimidine tracts (TOP) that encode protein machinery components and are frequently altered in cancer4. Significantly, mTOG dysregulation leads to aberrantly increased translation of 5' PES messenger RNA (mRNA) in malignant MDS-HSPCs and is clinically associated with leukaemic transformation and reduced patient survival. These findings define a critical role for tRFs and Ψ in difficult-to-treat subsets of MDS characterized by high risk of progression to acute myeloid leukaemia (AML).


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Células-Tronco Hematopoéticas/metabolismo , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Fatores de Iniciação de Peptídeos/metabolismo , Pseudouridina , RNA de Transferência/genética , RNA de Transferência/metabolismo , Proteínas de Ligação a RNA/genética
8.
Nat Cell Biol ; 23(12): 1224-1239, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34876685

RESUMO

Defective silencing of retrotransposable elements has been linked to inflammageing, cancer and autoimmune diseases. However, the underlying mechanisms are only partially understood. Here we implicate the histone H3.3 chaperone Daxx, a retrotransposable element repressor inactivated in myeloid leukaemia and other neoplasms, in protection from inflammatory disease. Loss of Daxx alters the chromatin landscape, H3.3 distribution and histone marks of haematopoietic progenitors, leading to engagement of a Pu.1-dependent transcriptional programme for myelopoiesis at the expense of B-cell differentiation. This causes neutrophilia and inflammation, predisposing mice to develop an autoinflammatory skin disease. While these molecular and phenotypic perturbations are in part reverted in animals lacking both Pu.1 and Daxx, haematopoietic progenitors in these mice show unique chromatin and transcriptome alterations, suggesting an interaction between these two pathways. Overall, our findings implicate retrotransposable element silencing in haematopoiesis and suggest a cross-talk between the H3.3 loading machinery and the pioneer transcription factor Pu.1.


Assuntos
Cromatina/patologia , Proteínas Correpressoras/genética , Transtornos Leucocíticos/congênito , Chaperonas Moleculares/genética , Mielopoese/genética , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Linfócitos B/citologia , Linhagem Celular , Cromatina/genética , Células-Tronco Hematopoéticas/citologia , Histonas/metabolismo , Humanos , Inflamação/patologia , Transtornos Leucocíticos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Retroelementos/genética , Dermatopatias/genética , Dermatopatias/imunologia , Dermatopatias/patologia
9.
Cell Rep ; 27(12): 3573-3586.e7, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216476

RESUMO

The X-linked DDX3X gene encodes an ATP-dependent DEAD-box RNA helicase frequently altered in various human cancers, including melanomas. Despite its important roles in translation and splicing, how DDX3X dysfunction specifically rewires gene expression in melanoma remains completely unknown. Here, we uncover a DDX3X-driven post-transcriptional program that dictates melanoma phenotype and poor disease prognosis. Through an unbiased analysis of translating ribosomes, we identified the microphthalmia-associated transcription factor, MITF, as a key DDX3X translational target that directs a proliferative-to-metastatic phenotypic switch in melanoma cells. Mechanistically, DDX3X controls MITF mRNA translation via an internal ribosome entry site (IRES) embedded within the 5' UTR. Through this exquisite translation-based regulatory mechanism, DDX3X steers MITF protein levels dictating melanoma metastatic potential in vivo and response to targeted therapy. Together, these findings unravel a post-transcriptional layer of gene regulation that may provide a unique therapeutic vulnerability in aggressive male melanomas.


Assuntos
Reprogramação Celular , RNA Helicases DEAD-box/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Regulação da Expressão Gênica , Melanoma/secundário , Biossíntese de Proteínas/genética , Animais , Proliferação de Células , RNA Helicases DEAD-box/genética , Feminino , Genes Ligados ao Cromossomo X , Humanos , Sítios Internos de Entrada Ribossomal , Metástase Linfática , Masculino , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Prognóstico
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