| 1. |
- Eldeeb, Mohamed, et al.
(författare)
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A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia
- 2023
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 42:2
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Gerber, Julia P., et al.
(författare)
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Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation
- 2021
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Ingår i: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 23:12, s. 1224-1239
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Guzzi, Nicola, et al.
(författare)
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Novel insights into the emerging roles of tRNA-derived fragments in mammalian development
- 2020
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Ingår i: RNA Biology. - : Informa UK Limited. - 1547-6286 .- 1555-8584. ; 17:8, s. 1214-1222
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 4. |
- Guzzi, Nicola
(författare)
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Post-transcriptional control of stem and cancer cell fate. New roles for an old RNA modification.
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Recent advances in high-throughput sequencing technologies uncovered widespread RNA modifications on coding and non-coding RNAs collectively refer to as the epitranscriptome. However, we are only now starting to appreciate the impact of the epitranscriptome in regulating cell biology. Among more than 150 RNA modifications, I focused on pseudouridine (Ψ) the most abundant single-nucleoside RNA modification. Ψ is dynamically regulated upon stress and has the potential to rapidly modulate gene expression by controlling RNA biogenesis, stability, function and translation. Still, the biological role of Ψ remains poorly understood. In this thesis, I studied the contribution of Ψ in stem and cancer cell biology, with the ultimate goal of illuminating new molecular programs controlling development and malignant transformation. Remarkably, in Paper I we uncovered an unanticipated role for the stem-cell-enriched Ψ synthase PUS7 in steering translation rate and dictating stem cell fate, through the modification of tRNA-derived fragments (tRF). In Paper II, we mechanistically dissected this new translational control pathway in stem cells and characterized the functional relevance of tRF dysregulation in hematological malignancies. In Paper III, we highlighted a critical interplay between the major oncogene MYC and PUS7, which converges on protein synthesis and steers MYC oncogenic program. In Paper IV, we characterized the impact of diet on small RNA composition in human sperm and identified a novel class of tRF selectively modulated upon diet intervention. Collectively, my work unravels new post-transcriptional mechanisms that govern gene expression in space and time to direct cell fate and malignant transformation. Ultimately, results from these studies will extend our knowledge on the molecular programs regulating development and tumorigenesis, with potentially broad clinical implications.
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| 5. |
- Guzzi, Nicola, et al.
(författare)
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Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome
- 2022
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Ingår i: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 24:3, s. 299-306
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Tidskriftsartikel (refereegranskat)abstract
- 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).
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| 6. |
- Guzzi, Nicola, et al.
(författare)
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Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells
- 2018
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 173:5, s. 26-1216
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Tidskriftsartikel (refereegranskat)abstract
- 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. Translational control in stem cells is orchestrated by pseudouridylation of specific tRNA-derived fragments, impacting stem cell commitment during key developmental processes.
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| 7. |
- Guzzi, Nicola, et al.
(författare)
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Stressin’ and slicin’ : stress-induced tRNA fragmentation codon-adapts translation to repress cell growth
- 2021
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Ingår i: EMBO Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 40:2
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Nätt, Daniel, et al.
(författare)
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Human sperm displays rapid responses to diet
- 2019
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Ingår i: PLoS biology. - San Francisco, CA United States : PUBLIC LIBRARY SCIENCE. - 1544-9173 .- 1545-7885. ; 17:12
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Phung, Bengt, et al.
(författare)
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The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma
- 2019
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 27:12, s. 7-3586
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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