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@ARTICLE{Rabany:305655,
      author       = {O. Rabany and S. Ben Dror and M. Arafat and H. Aharoni
                      Levitanus and Y. Halperin and V. Marchand and N. Romanovski
                      and N. Ussishkin and M. Livneh Golany and A. Reches and J.
                      Wexler and N. Mayorek and G. Monderer-Rothkoff and S.
                      Shifman and W. Mâmmer Bouhou and M. VanInsberghe and C.
                      Pauli$^*$ and C. Müller-Tidow and O. Karmi and Y. Livneh
                      and A. van Oudenaarden and Y. Motorin and D. Nachmani},
      title        = {{D}ynamic r{RNA} {M}ethylation {R}egulates {T}ranslation in
                      the {H}ematopoietic {S}ystem and is {E}ssential for {S}tem
                      {C}ell {F}itness.},
      journal      = {Blood},
      volume       = {nn},
      issn         = {0006-4971},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2025-02287},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {Self-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.},
      cin          = {A350},
      ddc          = {610},
      cid          = {I:(DE-He78)A350-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41191530},
      doi          = {10.1182/blood.2024028300},
      url          = {https://inrepo02.dkfz.de/record/305655},
}