Biology subjects

Cavaille, J.

Publications and source records attributed to Cavaille, J..

5 recordsLinked to original sources

bioRxiv2026

Evolutionary and biological insights into the paternally expressed Snord116-Ipw-Snord115 gene array at the imprinted Prader-Willi syndrome domain

Placental mammal-specific box C/D small nucleolar RNA (SNORD) genes within the imprinted human 15q11q13 domain have garnered increasing attention because their poorly understood roles in the brain and their potential involvement in Prader-Willi syndrome (PWS). Using two novel knockout (KO) mouse models, we demonstrate that combined deletion of Snord116 and Snord115 genes, but not the intervening Ipw ncRNA gene, leads to partially penetrant perinatal lethality (40-50%). Snord116/115-deficient neonates display postnatal growth impairment, hypoglycemia and endocrine dysregulation, including failure of the postnatal leptin surge. Despite showing no overt alterations in feeding behavior, adult Snord116/115-KO mice recapitulate most phenotypes previously reported in Snord116-KO models. RNA-seq analyses of the hypothalamus, prefrontal cortex and cerebellum reveal limited global changes. However, we observed upregulation of two of the most compelling putative RNA targets of Snord116 and Snord115 (Dgkk and Htr2c, respectively) in the postnatal hypothalamus. Nevertheless, no evidence was found to support efficient Snord115-guided ribose methylation of Htr2c mRNA. Finally, comparative analyses across 64 representative placental mammal species reveal that many PWS-associated SNORD genes, including SNORD115, display greater evolutionary changes than previously appreciated, raising questions about the functional relevance and evolutionary selective pressures that have shaped the diversification of certain family members across species. Overall, our study provides an unbiased re-assessment of the evolutionary, molecular and physiological significance of the paternally expressed Snord116-Ipw-Snord115 genomic interval and highlights the early postnatal period as a critical, yet largely underexplored, developmental window during which recently evolved SNORDs likely function as dispensable fine-tuners of gene expression.

genetics↗

bioRxiv2026

A novel class of tiny box C/D-like RNAs reveals hidden complexity in the mouse box C/D RNA repertoire

In recent years, the catalog of mammalian box C/D small nucleolar RNAs (SNORDs) has expanded considerably, with several hundred members now annotated in humans. Despite being a well-characterized family of antisense small noncoding RNAs, the full diversity of mammalian box C/D SNORDs remains incompletely understood. To address this, we combined deep sequencing of Fibrillarin- and Snu13-associated RNAs with systematic mining of a large collection of publicly available small RNA-seq datasets spanning diverse mouse tissues and cell types. This integrative approach uncovered an unexpectedly large repertoire of box C/D-like RNAs, comprising more than 20 000 distinct species. These RNAs display the defining hallmarks of intronic SNORDs but are expressed at low levels and exhibit poor evolutionary conservation. Strikingly, approximately 70% are only 20-50 nucleotides long, making them substantially shorter than canonical SNORDs. We designate this previously unrecognized class of box C/D-like RNAs as tiny SNORDs (tiSNORDs). Functional characterization of a representative 36-nucleotide tiSNORD demonstrates that, despite its reduced size, it retains nucleolar 2'-O-ribose methylation guide activity. The discovery of this previously unrecognized class of box C/D-like RNAs substantially expands the known repertoire of SNORDs and raises fundamental questions regarding their biogenesis, functional potential and evolutionary significance.

genetics↗

bioRxiv2026

Loss of SNORD115 mitigates SNORD116-driven sleep abnormalities in mouse models of Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by the loss of paternally expressed genes within the imprinted 15q11-q13 locus, which includes clusters of box C/D small nucleolar RNAs (SNORDs), notably the SNORD115 and SNORD116 gene families. Although paternally inherited SNORD116 deletions have been associated with sleep disturbances in patients and mouse models, the respective and combined contributions of SNORD115 and SNORD116 to sleep regulation remain unclear. Here, we combined polysomnographic recordings with quantitative analysis of hypothalamic neuronal populations to assess sleep-wake architecture, sleep homeostasis, and underlying circuit alterations in mice carrying paternal deletions of SNORD115, SNORD116, or both clusters. SNORD116 deletion was associated with a selective increase in REM sleep, particularly during the light phase and during recovery following sleep deprivation, without affecting slow-wave sleep or REM-associated theta activity. In contrast, SNORD115 deletion did not alter sleep. Unexpectedly, combined deletion of SNORD115 and SNORD116 did not reproduce the REM sleep phenotype observed in SNORD116-deficient mice, indicating that SNORD115 loss attenuates SNORD116-dependent REM sleep alterations. At the cellular level, melanin-concentrating hormone (MCH) neuron density was reduced in both SNORD116-KO and double SNORD116/115-KO mice, whereas hypocretin (Hcrt) neurons were preserved across genotypes. Notably, REM sleep alterations did not parallel MCH loss, as increased REM sleep was absent in double-KO animals despite comparable reduction in MCH neuron density. Transcriptomic analyses at ZT0 further revealed only limited changes in hypothalamic gene expression across models. Together, these findings reveal an unanticipated interaction between SNORD115 and SNORD116 in the regulation of REM sleep and uncover a dissociation between genetic alterations, neuronal circuit organization, and sleep phenotype. More broadly, they caution against inferring physiological functions or disease-relevant mechanisms from single SNORD deletions within complex imprinted loci, and indicate that current mouse models may not faithfully capture sleep alterations associated with PWS.

neuroscience↗

bioRxiv2022

Antisense pairing and SNORD13 structure guide RNA cytidine acetylation

N4-acetylcytidine (ac4C) is an RNA nucleobase found in all domains of life. Establishment of ac4C in helix 45 (h45) of human 18S ribosomal RNA (rRNA) requires the combined activity of the acetyltransferase NAT10 and the box C/D snoRNA SNORD13. However, the molecular mechanisms governing RNA-guided nucleobase acetylation in humans remain unexplored. Here we report two assays that enable the study of SNORD13-dependent RNA acetylation in human cells. First, we demonstrate that ectopic expression of SNORD13 rescues h45 in a SNORD13 knockout cell line. Next, we show mutant snoRNAs can be used in combination with nucleotide resolution ac4C sequencing to define structure and sequence elements critical for SNORD13 function. Finally, we develop a second method that reports on the substrate specificity of endogenous NAT10-SNORD13 via mutational analysis of an ectopically-expressed pre-rRNA substrate. By combining mutational analysis of these reconstituted systems with nucleotide resolution ac4C sequencing, our studies reveal plasticity in the molecular determinants underlying RNA-guided cytidine acetylation that is distinct from deposition of other well-studied rRNA modifications (e.g. pseudouridine). Overall, our studies provide a new approach to reconstitute RNA-guided cytidine acetylation in human cells as well as nucleotide resolution insights into the mechanisms governing this process. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biochemistry↗

bioRxiv2021

Probing small ribosomal subunit RNA helix 45 acetylation across eukaryotic evolution

NAT10 is an essential enzyme that catalyzes the formation of N4-acetylcytidine (ac4C) in eukaryotic transfer RNA (tRNA) and 18S ribosomal RNA (rRNA). Recent studies in human cells suggested that rRNA acetylation is dependent on SNORD13, a non-canonical box C/D small nucleolar RNA (SNORD) predicted to base-pair with 18S rRNA via two antisense elements. However, the selectivity of SNORD13-dependent cytidine acetylation and its relationship to NAT10s essential function in pre-rRNA processing remain to be defined. Here, we used CRISPR-Cas9 genome editing to formally demonstrate that SNORD13 is required for acetylation of a single cytidine residue of human and zebrafish 18S rRNA. In-depth characterization revealed that SNORD13-dependent ac4C is dispensable for yeast or human cell growth, ribosome biogenesis, translation, and the development of multicellular metazoan model organisms. This loss of function analysis inspired a cross-evolutionary survey of the eukaryotic rRNA acetylation machinery that led to the characterization of many novel SNORD13 genes in phylogenetically-distant metazoans and more deeply rooted photosynthetic organisms. This includes an atypical SNORD13-like RNA in D. melanogaster which appears to guide ac4C to 18S rRNA helix 45 despite lacking one of the two rRNA antisense elements. Finally, we discover that C. elegans 18S rRNA is not acetylated despite the presence of an essential NAT10 homolog. Altogether, our findings shed light on the molecular mechanisms underlying SNORD13-mediated rRNA acetylation across the eukaryotic tree of life and raise new questions regarding the biological function and evolutionary persistence of this highly conserved rRNA base modification.

molecular biology↗