Abstract
Box C/D-type small nucleolar RNAs (snoRNAs) are functional RNAs responsible for mediating 2′-O-ribose methylation of ribosomal RNAs (rRNAs) within the nucleolus. In the past years, evidence for the involvement of human U50 snoRNA in tumorigenesis has been accumulating. We previously identified U50HG, a non-protein-coding gene that hosted a box C/D-type U50 snoRNA, in a chromosomal breakpoint in a human B-cell lymphoma. Mouse genome analysis revealed four mouse U50 (mU50) host-genes: three mU50HG-a gene variants that were clustered in the genome and an mU50HG-b gene that we supposed to be the U50HG ortholog. In this study, to investigate the physiological importance of mU50 snoRNA and its involvement in tumorigenesis, we eliminated mU50 snoRNA sequences from the mU50HG-b gene. The established mouse line (ΔmU50(HG-b)) showed a significant reduction of mU50 snoRNA expression without alteration of the host-gene length and exon-intron structure, and the corresponding target rRNA methylation in various organs was reduced. Lifelong phenotypic monitoring showed that the ΔmU50(HG-b) mice looked almost normal without accelerated tumorigenicity; however, a notable difference was the propensity for anomalies in the lymphoid organs. Transcriptome analysis showed that dozens of genes, including heat shock proteins, were differentially expressed in ΔmU50(HG-b) mouse lymphocytes. This unique model of a single snoRNA knockdown with intact host-gene expression revealed further new insights into the discrete transcriptional regulation of multiple mU50 host-genes and the complicated dynamics involved in organ-specific processing and maintenance of snoRNAs.
Highlights
Small nucleolar RNAs are one of the abundant nonprotein-coding RNA species (.300 snoRNAs have been found in human) that are responsible for the maturation of ribosomal RNAs within the nucleolus [1,2]. snoRNAs achieve site-specific nucleotide modification by base-pairing to complementary sequences on rRNA precursors
We found that the deletion of mU50HG-b-encoded mouse U50 (mU50) snoRNA sequences resulted in a marked reduction in the quantity of mU50 snoRNA and methylation of the target rRNA, and that the perturbation of mU50 snoRNA was not crucial for growth and lifespan but yielded subtle anomalies and gene modulation in the lymphoid organs
When each of the intron-encoded mU50 snoRNA sequences in the mU50HG-a hostgenes were compared, we found three single nucleotide polymorphisms in the middle of the snoRNA sequences that did not correspond to the complementary sequence to the rRNA target
Summary
Small nucleolar RNAs (snoRNAs) are one of the abundant nonprotein-coding RNA species (.300 snoRNAs have been found in human) that are responsible for the maturation of ribosomal RNAs (rRNAs) within the nucleolus [1,2]. snoRNAs achieve site-specific nucleotide modification by base-pairing to complementary sequences on rRNA precursors. SnoRNAs achieve site-specific nucleotide modification by base-pairing to complementary sequences on rRNA precursors. Based on the conserved nucleotide sequences and their function, snoRNAs are grouped into two classes: box C/D-type snoRNAs and box H/ACA-type snoRNAs that catalyze 29-O-ribose methylation and pseudouridylation, respectively [3,4,5,6]. Most snoRNA host-genes encode proteins that play a role in the translation machinery of cells. With respect to the physiological roles of snoRNAs, loss-offunction studies for a single snoRNA in yeast have so far demonstrated that the snoRNA-assisted rRNA modifications were not critical but, in part, caused subtle phenotypic alterations in cell growth [14,15]. Molecular genetic approaches have rarely been used to explore the physiological and pathogenetic importance of individual snoRNAs in higher organisms [16]
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