ERP130584 PRJEB46399 ena-STUDY-Lorraine University-17-07-2021-13:37:15:259-283 RNASeq: FTSJ1 tRNA Nm-MTase: new human targets and role in the regulation of brain-specific genes FTSJ1 is a phyllogenetically conserved human 2'-O-methyltransferase (Nm-MTase) which modifies position 32 as well as the wobble position 34 in the anticodon Loop (ACL) of specific tRNAs: tRNAPhe, tRNATrp and tRNALeu. FTSJ1's loss of function has been linked to non-syndromic X-linked intellectual disability (NSXLID), and more recently to cancers. However, the exact nature of the molecular mechanisms underlying FTSJ1-related pathogenesis are unknown and a potential extended variety of FTSJ1's tRNA targets hasn't been fully addressed yet. Here, we report on the first unbiased RiboMethSeq analysis of the Nm profiles of the totality of the human tRNA population directly on cells derived from NSXLID patients' blood bearing various characterized loss of function mutations in FTSJ1. In addition, we reported a novel FTSJ1 pathogenic variant from a NSXLID patient bearing a de novo mutation in the FTSJ1 gene. Some of the newly identified FTSJ1's tRNA targets are conserved in Drosophila as shown by our previous study on the fly homologues Trm7_32 and Trm7_34, whose loss affects small RNA silencing pathways. In the current study, we reveal through next generation sequencing a conserved deregulation in both the miRNA and mRNA populations when FTSJ1 function is compromised. In addition, a cross-analysing between these two data sets obtained in FTSJ1 mutant highlighted the upregulated miR10a-5p who has the capacity to target the SPARC gene mRNA, downregulated in FTSJ1 mutant cells, suggesting that FTSJ1 loss may influence gene expression deregulation through modulated miRNA silencing. A GO enrichment analysis of the deregulated mRNAs matched primarily in brain morphogenesis terms, followed by metabolism and translation related ones. In parallel, the deregulated miRNAs are mostly known for their implication in brain functioning and cancers. Based on these results, we suggest that miRNA silencing variations may play a part in the pathological mechanisms of FTSJ1-dependent NSXLID. Finally, our results highlight miR-181a-5p as a potential companion diagnostic test in clinical settings for FTSJ1-related intellectual disability. FTSJ1 patients RNASeq FTSJ1 is a phyllogenetically conserved human 2'-O-methyltransferase (Nm-MTase) which modifies position 32 as well as the wobble position 34 in the anticodon Loop (ACL) of specific tRNAs: tRNAPhe, tRNATrp and tRNALeu. FTSJ1's loss of function has been linked to non-syndromic X-linked intellectual disability (NSXLID), and more recently to cancers. However, the exact nature of the molecular mechanisms underlying FTSJ1-related pathogenesis are unknown and a potential extended variety of FTSJ1's tRNA targets hasn't been fully addressed yet. Here, we report on the first unbiased RiboMethSeq analysis of the Nm profiles of the totality of the human tRNA population directly on cells derived from NSXLID patients' blood bearing various characterized loss of function mutations in FTSJ1. In addition, we reported a novel FTSJ1 pathogenic variant from a NSXLID patient bearing a de novo mutation in the FTSJ1 gene. Some of the newly identified FTSJ1's tRNA targets are conserved in Drosophila as shown by our previous study on the fly homologues Trm7_32 and Trm7_34, whose loss affects small RNA silencing pathways. In the current study, we reveal through next generation sequencing a conserved deregulation in both the miRNA and mRNA populations when FTSJ1 function is compromised. In addition, a cross-analysing between these two data sets obtained in FTSJ1 mutant highlighted the upregulated miR10a-5p who has the capacity to target the SPARC gene mRNA, downregulated in FTSJ1 mutant cells, suggesting that FTSJ1 loss may influence gene expression deregulation through modulated miRNA silencing. A GO enrichment analysis of the deregulated mRNAs matched primarily in brain morphogenesis terms, followed by metabolism and translation related ones. In parallel, the deregulated miRNAs are mostly known for their implication in brain functioning and cancers. Based on these results, we suggest that miRNA silencing variations may play a part in the pathological mechanisms of FTSJ1-dependent NSXLID. Finally, our results highlight miR-181a-5p as a potential companion diagnostic test in clinical settings for FTSJ1-related intellectual disability. ENA-FIRST-PUBLIC 2023-01-05 ENA-LAST-UPDATE 2023-01-05