ZNHIT3 regulates translation to ensure mouse preimplantation development [SMARMseq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE267991 | GEO | 2025/11/18
REPOSITORIES: GEO
Dataset's files
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| GSE267991_RAW.tar | Raw | |||
| GSE267991_RiboMeth_Scores_of_rRNA_Bases_for_All_Samples.csv.gz | Csv | |||
| filelist.txt | Txt |
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Project description:Upon fertilization, the mouse zygotic genome is activated, accompanied by degradation of maternal proteins and RNAs. The development programs are built by accumulation of proteins from zygotic genes to guide the early cell fate commitments. Box C/D snoRNA ribonucleoprotein (snoRNP) complex is required for rRNA biogenesis, ribosome assembly and pre-mRNA splicing necessary for protein translation. Zinc finger, HIT type 3 (encoded by Znhit3) was previously identified to be one component in the assembly of the box C/D snoRNP complex. Using gene-edited mice, we identify Znhit3 as a pioneer embryonic gene whose ablation prevents mouse embryos development beyond the morula stage due to reduced protein translation. Znhit3 ablation impairs snoRNA and rRNA levels which leads to defects of ribosomes and failure of mRNA splicing. Our results provide clear evidence that ZNHIT3 is required for mouse preimplantation development by controlling proper mRNA translation into protein.
2025-11-18 | GSE267997 | GEO
Project description:Upon fertilization, the mouse zygotic genome is activated, accompanied by degradation of maternal proteins and RNAs. The development programs are built by accumulation of proteins from zygotic genes to guide the early cell fate commitments. Box C/D snoRNA ribonucleoprotein (snoRNP) complex is required for rRNA biogenesis, ribosome assembly and pre-mRNA splicing necessary for protein translation. Zinc finger, HIT type 3 (encoded by Znhit3) was previously identified to be one component in the assembly of the box C/D snoRNP complex. Using gene-edited mice, we identify Znhit3 as a pioneer embryonic gene whose ablation prevents mouse embryos development beyond the morula stage due to reduced protein translation. Znhit3 ablation impairs snoRNA and rRNA levels which leads to defects of ribosomes and failure of mRNA splicing. Our results provide clear evidence that ZNHIT3 is required for mouse preimplantation development by controlling proper mRNA translation into protein.
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Project description:Glioblastoma (GBM) ranks among the most lethal of human cancers, containing glioma stem cells (GSCs) that display therapeutic resistance. Here, we report that the lncRNA INHEG is highly expressed in GSCs compared to differentiated glioma cells (DGCs) and promotes GSC self-renewal through control of rRNA 2’-O-methylation. INHEG induces the interaction between a novel SUMO E3 ligase TAF15 and NOP58, a core component of snoRNP that guides rRNA methylation, to regulate NOP58 sumoylation and accelerate the C/D box snoRNP assembly. INHEG activation enhances rRNA 2’-O-methylation, thereby increasing the translation of oncogenic proteins including EGFR and IGF1R in glioma cells. Taken together, this study identifies a lncRNA that connects snoRNP-guided rRNA 2’-O-methylation to upregulated protein translation in GSCs, supporting a new axis for potential therapeutic targeting of gliomas.
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Project description:ZNHIT3 (zinc finger HIT type containing protein 3) is an evolutionarily conserved protein required for ribosome biogenesis by mediating the assembly of small nucleolar RNAs (snoRNAs) of class C/D into ribonucleoprotein complexes (snoRNPs). Missense mutations in the gene encoding ZNHIT3 protein have been previously reported to cause PEHO syndrome, a severe neurodevelopmental disorder typically presenting after birth. We present here the case of two fetuses from a single family who presented with isolated hydrops during the early second trimester of pregnancy, resulting in intrauterine demise. Autopsy revealed no associated malformation. Through whole-genome quartet analysis, we identified two novel variants within the ZNHIT3 gene, both inherited from healthy parents and occurring as compound heterozygotes in both fetuses. The c.40T>C p.Cys14Arg variant originated from the father, while the c.251_254delAAGA r.? p.? variant was of maternal origin. Western capillary analysis of ZNHIT3 protein in lymphoblastoid cell lines of the parents shows that the parental c.40T>C p.Cys14Arg variant causes a significant drop in steady-state ZNHIT3 protein level. Analysis of the variants in human cell culture models reveals that both variants reduce cell growth, albeit to different extents, and impact the protein's stability and function in distinct ways. The c.251_254delAAGA results in production of a stable form of ZNHIT3 that lacks a domain required for mediating snoRNP biogenesis, whereas the c.40T>C p.Cys14Arg variation behaves similarly to the previously described PEHO-associated ZNHIT3 variants that destabilize the protein. Interestingly, both variations lead to a marked decrease in specific box C/D snoRNA levels, reduced rRNA levels and cellular translation. Analysis of rRNA methylation pattern in fetus samples reveals distinct sites of hypo 2’-O-methylation. RNA-seq analysis of undifferentiated and differentiated SHSY5Y cells transfected with the ZNHIT3 variants reveals differential expression of a set of genes, many of which are associated with developmental processes and RNA binding compared to cells expressing wild-type ZNHIT3. In summary, this work adds two novel ZNHIT3 variants to the other human disease-linked variants of this protein and describes the molecular defects caused by these pathogenic variants.
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Project description:Osteoarthritis (OA) is a chronic debilitating joint disease which is strongly associated with ageing. OA involves pathological cellular processes in all joint structures and affects articular cartilage integrity, leading to dysfunctional joint articulation. The biomolecular processes that catalyze the disturbances in the articular chondrocyte phenotype leading to OA are poorly understood, and it is expected that a comprehensive understanding of the avenues leading to catabolic changes and disruption of articular chondrocyte homeostasis will provide important cues for future treatments of the condition. Chondrocytes are specialized secretory cells with highly active protein translational machinery, enabling the synthesis and maintenance of the protein-rich cartilage extracellular matrix (ECM). Disturbances in chondrocyte protein translation in cartilage development and OA are connected to mTOR activity, ER stress, unfolded protein response (UPR)and CHOP-mediated apoptosis. These responses change the downstream translational activity of the biosynthesized ribosome. The assembled mammalian ribosome is built from ribosomal RNAs (rRNAs), together with more than 80 different protein subunits. At the heart of the ribosome, the 18S rRNA guides the decoding of the mRNA message, while an ancient ribozyme activity in the 28S rRNA forms the core of the peptidyltransferase center that polymerizes the amino acid sequence encoded by the mRNA into functional proteins. Post-transcriptional maturation of rRNAs is an integral part of the biosynthesis of ribosomes and ribonucleolytic processing of the major 47S rRNA precursor into mature 18S, 5.8S, and 28S rRNAs is rate limiting for ribosome biogenesis. The U3 small nucleolar RNA (snoRNA) is an evolutionarily highly conserved box C/D-class snoRNA which catalyzes the endoribonucleolytic processing of the 5’ external transcribed spacer (ETS) of the 47S pre-rRNA by base complementarity-guided pre-rRNA substrate recognition and plays a crucial role in the maturation of 18S rRNA. Although extensively studied in yeast, it was only recently demonstrated that U3 snoRNA is indispensable for rRNA maturation in human cells. Pathways controlling ribosome activity have previously been described in the regulation of chondrocyte homeostasis. We here now postulate that not only ribosome activity is involved in chondrocyte homeostasis, but that OA pathophysiological situations can also cause alterations in chondrocyte ribosome biogenesis with consequences for cellular protein translation. Since U3 snoRNA-driven rRNA production is rate-limiting in ribosome biogenesis, we hypothesized that the U3 snoRNA is critical for chondrocyte homeostasis. In this study we therefor aimed to determine whether OA pathophysiological conditions interact with chondrocyte U3 snoRNA levels, thereby influencing rRNA levels and chondrocyte translation capacity.
2020-08-21 | PXD017253 | Pride
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2016-01-07 | GSE76578 | GEO
Project description:Background: In recent years, a variety of small RNAs derived from other RNAs with well-known functions such as tRNAs and snoRNAs, have been identified. The functional relevance of these RNAs is largely unknown. To gain insight into the complexity of snoRNA processing and the functional relevance of snoRNA-derived small RNAs, we sequenced long and short RNAs, small RNAs that co-precipitate with the Argonaute 2 protein and RNA fragments obtained in photoreactive nucleotide-enhanced crosslinking and immunoprecipitation (PAR-CLIP) of core snoRNA-associated proteins. Results: Analysis of these data sets revealed that many loci in the human genome reproducibly give rise to C/D box-like snoRNAs, whose expression and evolutionary conservation are typically less pronounced relative to the snoRNAs that are currently catalogued. We further found that virtually all C/D box snoRNAs are specifically processed inside the regions of terminal complementarity, retaining in the mature form only 4-5 nucleotides upstream of the C box and 2-5 nucleotides downstream of the D box. Sequencing of the total and Argonaute 2-associated populations of small RNAs revealed that despite their cellular abundance, C/D box-derived small RNAs are not efficiently incorporated into the Ago2 protein. Conclusions: We conclude that the human genome encodes a large number of snoRNAs that are processed along the canonical pathway and expressed at relatively low levels. Generation of snoRNA-derived processing products with alternative, particularly miRNA-like, functions appears to be uncommon. PAR-CLIP profiling for snoRNP core proteins NOP56, NOP58, Fibrillarin, and Dyskerin in HEK293 cells. Small RNA profiling using RNA-seq in HEK293 and HeLa cells, small RNA profiling using IP-seq of Ago2 associated small RNAs.
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