Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization

Abstract

We have identified three C͞D-box small nucleolar RNAs (snoRNAs) and one H͞ACA-box snoRNA in mouse and human. In mice, all four snoRNAs (MBII-13, MBII-52, MBII-85, and MBI-36) are exclusively expressed in the brain, unlike all other known snoRNAs. Two of the human RNA orthologues (HBII-52 and HBI-36) share this expression pattern, and the remainder, HBII-13 and HBII-85, are prevalently expressed in that tissue. In mice and humans, the brain-specific H͞ACA box snoRNA (MBI-36 and HBI-36, respectively) is intronencoded in the brain-specific serotonin 2C receptor gene. The three human C͞D box snoRNAs map to chromosome 15q11-q13, within a region implicated in the Prader-Willi syndrome (PWS), which is a neurogenetic disease resulting from a deficiency of paternal gene expression. Unlike other C͞D box snoRNAs, two snoRNAs, HBII-52 and HBII-85, are encoded in a tandemly repeated array of 47 or 24 units, respectively. In mouse the homologue of HBII-52 is processed from intronic portions of the tandem repeats. Interestingly, these snoRNAs were absent from the cortex of a patient with PWS and from a PWS mouse model, demonstrating their paternal imprinting status and pointing to their potential role in the etiology of PWS. Despite displaying hallmarks of the two families of ubiquitous snoRNAs that guide 2-O-ribose methylation and pseudouridylation of rRNA, respectively, they lack any telltale rRNA complementarity. Instead, brain-specific C͞D box snoRNA HBII-52 has an 18-nt phylogenetically conserved complementarity to a critical segment of serotonin 2C receptor mRNA, pointing to a potential role in the processing of this mRNA. T he biogenesis of eukaryotic ribosomes involves a complex rRNA processing pathway mostly taking place in a specialized subnuclear compartment, the nucleolus. Pre-rRNA maturation includes, in addition to a series of endonucleolytic and exonucleolytic cleavages, the covalent modification of a definite subset of rRNA nucleotides, essentially by 2Ј-O-ribose methylation and pseudouridylation. Each of these modifications is found at about 100 sites per vertebrate ribosome (1). Although these modifications are phylogenetically conserved and restricted to the most highly conserved and functionally important regions of rRNA, their function remains largely unknown. Spliceosomal small nuclear RNAs (snRNAs) also contain a number of conserved 2Ј-Omethylated nucleotides and pseudouridines, confined to snRNA sequences critical for splicing, i.e., involved in contacts with premRNA or other snRNAs (2). Remarkably, nucleotide modifications in the 5Ј terminal region of U2 snRNA are required for assembly of a functional U2 sn-ribonucleoprotein particle (3).The nucleolus contains a large number of small, metabolically stable RNAs, termed small nucleolar RNAs (snoRNAs) that fall into two major classes, the C͞D box and H͞ACA box snoRNAs, designated after common sequence motifs involved in the assembly of sno-ribonucleoprotein particles. Although each class includes a small number of snoRNAs required for definite pre-rRNA cl...

Highly restricted deletion of the SNORD116 region is implicated in Prader–Willi Syndrome

“…5 This finding is also in accordance with the recent data demonstrating the regulatory role of GC skew repeat elements or long non-coding RNA (116HG) derived from the SNORD116 region. 14,16 This case therefore strengthens an evidence for the role of the SNORD116 region that has recently been highlighted in the molecular pathophysiology of PWS, [6][7][8] either as fully processed box C/D snoRNA species or as long non-coding host transcripts (116HG). [16][17][18][19] Next step will be to investigate the functions of these RNAs and their role in the pathogenesis of PWS.…”

Prader-Willi syndrome

“…The UBE3A antisense transcript also arises from transcription of SNURF-SNRPN and is thought to lead to the repression of the paternally inherited UBE3A gene in humans and mice. [98][99][100] The snoRNAs are present in single copy except for SNORD116 (previously named HBII-85) and SNORD115 (previously named HBII-52), which are present in 29 and 42 copies, respectively. It is thought that the snoRNAs are probably involved in the modification of mRNA by alternative splicing and that each snoRNA gene might have multiple targets.…”

Small RNAs in Human Brain Development and Disorders

“…Small nucleolar RNA (snoRNA) (~300 of known human snoRNAs of 60 300 nt in length) promote chemical mod ifications of other RNAs, mainly, non protein coding RNAs. However, some of the snoRNAs have complemen tary sequences in mRNA (e.g., to sequence harboring adenosite to ionosin RNA editing site of the serotonin 2C receptor gene) [1], and, therefore, may contribute to modification of mRNA of some neurogenes. Another abundant class of non coding RNA are tiny RNAs (~19 25 nt) produced from longer double stranded RNA.…”