Ribosomal RNA 2'-O-methylation dynamics during development and differentiation impact cell fate decisions

Ribosomes, essential for the interpretation of genetic information, are not identical machineries without any control over the translation process. We and others have unveiled the natural diversity of ribosomes and how this impacts their function. One source of ribosome heterogeneity is the 2'-O-methylation (2'-O-me) of ribosomal RNA (rRNA). Here, we show that the rRNA 2'-O-me profile dynamically changes during mouse brain development and the directed differentiation of human embryonic stem cells (hESCs). Moreover, we demonstrate that the removal of one specific 2'-O-me, at position 28S:U3904, prompts hESCs to become early neural progenitor cells and favours hindbrain differentiation. Further analyses point towards an increased binding to FMRP and better translation of WNT pathway mRNAs by ribosomes devoid of 28S:U3904-me as the underlying mechanism for this identity shift. Overall design: Embryonic mouse brain cortex at seven stages of differentiation, as well as hippocampus, cerebellum, and olfactory bulb at the neonate and adult stage, and hESCs at the pluripotency stage and subjected to directed differentiation into ecto-, endo-, and mesoderm were analysed as biological triplicates for their rRNA 2'-O-me profile using RiboMeth-seq.