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000305655 1001_ $$aRabany, Ofri$$b0
000305655 245__ $$aDynamic rRNA Methylation Regulates Translation in the Hematopoietic System and is Essential for Stem Cell Fitness.
000305655 260__ $$aWashington, DC$$bAmerican Society of Hematology$$c2025
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000305655 520__ $$aSelf-renewal and differentiation are at the basis of hematopoiesis. While it is known that tight regulation of translation is vital for hematopoietic stem cells' (HSCs) biology, the mechanisms underlying translation regulation across the hematopoietic system remain obscure. Here we reveal a novel mechanism of translation regulation in the hematopoietic hierarchy, which is mediated by ribosomal RNA (rRNA) methylation dynamics. Using ultra-low input ribosome-profiling, we characterized cell-type-specific translation capacity during erythroid differentiation. We found that translation efficiency changes progressively with differentiation and can distinguish between discrete cell populations as well as to define differentiation trajectories. To reveal the underlying mechanism, we performed comprehensive mapping of the most abundant rRNA modification - 2'-O-methyl (2'OMe). We found that, like translation efficiency, 2'OMe dynamics followed a distinct trajectory during erythroid differentiation.Genetic perturbation of individual 2'OMe sites demonstrated their distinct roles in modulating proliferation and differentiation. By combining CRISPR screening, molecular and functional analyses, we identified a specific methylation site, 28S-Gm4588, which is progressively lost during differentiation, as a key regulator of HSC self-renewal. We showed that low methylation at this site led to translational skewing, mediated mainly by codon frequency, which promoted differentiation. Functionally, HSCs with diminished 28S-Gm4588 methylation exhibited impaired self-renewal capacity ex-vivo, and loss of fitness in-vivo in bone marrow transplantations.Extending our findings beyond the hematopoietic system, we also found distinct dynamics of 2'OMe profiles during differentiation of non-hematopoietic stem cells. Our findings reveal rRNA methylation dynamics as a general mechanism for cell-type-specific translation, required for cell function and differentiation.
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000305655 7001_ $$aBen Dror, Sivan$$b1
000305655 7001_ $$aArafat, Maram$$b2
000305655 7001_ $$aAharoni Levitanus, Hadar$$b3
000305655 7001_ $$00009-0009-7378-4946$$aHalperin, Yudit$$b4
000305655 7001_ $$00000-0002-8537-1139$$aMarchand, Virginie$$b5
000305655 7001_ $$aRomanovski, Nikolai$$b6
000305655 7001_ $$00009-0006-6357-7212$$aUssishkin, Noga$$b7
000305655 7001_ $$aLivneh Golany, Maayan$$b8
000305655 7001_ $$aReches, Adi$$b9
000305655 7001_ $$aWexler, Judith$$b10
000305655 7001_ $$aMayorek, Nina$$b11
000305655 7001_ $$aMonderer-Rothkoff, Galya$$b12
000305655 7001_ $$00000-0003-4071-5361$$aShifman, Sagiv$$b13
000305655 7001_ $$aMâmmer Bouhou, Widad$$b14
000305655 7001_ $$00000-0001-8418-4393$$aVanInsberghe, Michael$$b15
000305655 7001_ $$0P:(DE-He78)09cd3a09acde3c9d99ac67be925b517c$$aPauli, Cornelius$$b16$$udkfz
000305655 7001_ $$aMüller-Tidow, Carsten$$b17
000305655 7001_ $$00000-0002-8684-7039$$aKarmi, Ola$$b18
000305655 7001_ $$00000-0002-0434-4201$$aLivneh, Yoav$$b19
000305655 7001_ $$avan Oudenaarden, Alexander$$b20
000305655 7001_ $$00000-0002-8018-334X$$aMotorin, Yuri$$b21
000305655 7001_ $$aNachmani, Daphna$$b22
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