| 1. |
- 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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| 2. |
- Jassinskaja, Maria, et al.
(författare)
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Ontogenic shifts in cellular fate are linked to proteotype changes in lineage-biased hematopoietic progenitor cells
- 2021
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 34:12
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Tidskriftsartikel (refereegranskat)abstract
- The process of hematopoiesis is subject to substantial ontogenic remodeling that is accompanied by alterations in cellular fate during both development and disease. We combine state-of-the-art mass spectrometry with extensive functional assays to gain insight into ontogeny-specific proteomic mechanisms regulating hematopoiesis. Through deep coverage of the cellular proteome of fetal and adult lympho-myeloid multipotent progenitors (LMPPs), common lymphoid progenitors (CLPs), and granulocyte-monocyte progenitors (GMPs), we establish that features traditionally attributed to adult hematopoiesis are conserved across lymphoid and myeloid lineages, whereas generic fetal features are suppressed in GMPs. We reveal molecular and functional evidence for a diminished granulocyte differentiation capacity in fetal LMPPs and GMPs relative to their adult counterparts. Our data indicate an ontogeny-specific requirement of myosin activity for myelopoiesis in LMPPs. Finally, we uncover an ontogenic shift in the monocytic differentiation capacity of GMPs, partially driven by a differential expression of Irf8 during fetal and adult life.
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| 3. |
- Mattebo, Alexander, et al.
(författare)
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Yippee like 4 (Ypel4) is essential for normal mouse red blood cell membrane integrity
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The YPEL family genes are highly conserved across a diverse range of eukaryotic organisms and thus potentially involved in essential cellular processes. Ypel4, one of five YPEL family gene orthologs in mouse and human, is highly and specifically expressed in late terminal erythroid differentiation (TED). In this study, we investigated the role of Ypel4 in murine erythropoiesis, providing for the first time an in-depth description of a Ypel4-null phenotype in vivo. We demonstrated that the Ypel4-null mice displayed a secondary polycythemia with macro- and reticulocytosis. While lack of Ypel4 did not affect steady-state TED in the bone marrow or spleen, the anemia-recovering capacity of Ypel4-null cells was diminished. Furthermore, Ypel4-null red blood cells (RBC) were cleared from the circulation at an increased rate, demonstrating an intrinsic defect of RBCs. Scanning electron micrographs revealed an ovalocytic morphology of Ypel4-null RBCs and functional testing confirmed reduced deformability. Even though Band 3 protein levels were shown to be reduced in Ypel4-null RBC membranes, we could not find support for a physical interaction between YPEL4 and the Band 3 protein. In conclusion, our findings provide crucial insights into the role of Ypel4 in preserving normal red cell membrane integrity.
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| 4. |
- Vajrychova, M., et al.
(författare)
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Comprehensive proteomic investigation of infectious and inflammatory changes in late preterm prelabour rupture of membranes
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Preterm prelabour rupture of membranes beyond the 34th week of gestation (late PPROM) is frequently associated with the risk of the microbial invasion of the amniotic fluid (MIAC) and histological chorioamnionitis (HCA). Hence, we employed a Tandem Mass Tag-based approach to uncover amniotic fluid proteome response to the presence of MIAC and HCA in late PPROM. Protein dysregulation was associated with only five cases in the group of 15 women with confirmed MIAC and HCA. Altogether, 138 amniotic fluid proteins were changed in these five cases exclusively. These proteins were particularly associated with excessive neutrophil responses to infection, such as neutrophil degranulation and extracellular trap formation. We believe that the quantification of these proteins in amniotic fluid may assist in revealing women with the highest risk of excessive inflammatory response in late PPROM.
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