title: Generation of a mouse model with down-regulated U50 snoRNA (SNORD50) expression and its organ-specific phenotypic modulation.
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.
authors.affiliation: Department of Pathology, School of Life Dentistry, The Nippon Dental University, Tokyo, Japan.
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Soeno
authors.forename: Kazuya
authors.initials: K
authors.lastname: Fujita
authors.forename: Tomoo
authors.initials: T
authors.lastname: Kudo
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kakuta
authors.forename: Yuji
authors.initials: Y
authors.lastname: Taya
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Shimazu
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Tanaka-Fujita
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kubo
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Shigeo
authors.initials: S
authors.lastname: Mori
authors.forename: Takaaki
authors.initials: T
authors.lastname: Aoba
mesh_terms: D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity / Q000235:genetics*; D010641:Phenotype; D010802:Phylogeny; D020537:RNA, Small Nucleolar / Q000737:chemistry / Q000145:classification / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid
chemical_list: D020537:RNA, Small Nucleolar