Impaired spermatogenesis, muscle and erythrocyte function in U12 intron splicing-defective Zrsr1 mutant mice
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ABSTRACT:
PROVIDER: PRJEB14620 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR1474930_1.fastq.gz | Fastqsanger.gz | |||
| ERR1474930_2.fastq.gz | Fastqsanger.gz | |||
| ERR1474940_1.fastq.gz | Fastqsanger.gz | |||
| ERR1474940_2.fastq.gz | Fastqsanger.gz | |||
| ERR1474931_1.fastq.gz | Fastqsanger.gz |
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Project description:We analysed the gene expression in testis of Zrsr1 mutant mice. We generated mutant mice containing truncating mutations within the RNA-recognition motif (RRM) in Zrsr1 locus. The RNAs of testes from 4 WT and 5 Zrsr1 mutant mice at day 15, immediately after the peak of expression of Zrsr1 in developing testis, were prepared and sequenced in order to identify and characterize the RNAs regulated by Zrsr1 in developing testis.
2018-04-03 | E-MTAB-4872 | biostudies-arrayexpress
Project description:Recurrent loss-of-function mutations of spliceosome gene, ZRSR2, occur in myelodysplastic syndromes (MDS). Mutation/loss of ZRSR2 in human myeloid cells primarily causes impaired splicing of the U12-type introns. To investigate further the role of this splice factor in splicing and hematopoietic development, we generated mice lacking ZRSR2. Unexpectedly, Zrsr2-deficient mice developed normal hematopoiesis with no abnormalities in myeloid differentiation evident in either young or ≥1-year old knockout mice. Repopulation ability of Zrsr2-deficient hematopoietic stem cells was also unaffected in reconstitution assays. Myeloid progenitors lacking ZRSR2 exhibited mis-splicing of U12-type introns, however, this phenotype was moderate compared to the ZRSR2-deficient human cells. Our investigations revealed that a closely related homolog, Zrsr1, expressed in the murine hematopoietic cells, but not human, contributes to splicing of U12-type introns. Depletion of Zrsr1 in Zrsr2 KO myeloid cells exacerbated retention of the U12-type introns, thus highlighting a collective role of ZRSR1 and ZRSR2 in murine U12-spliceosome. We also demonstrate that aberrant retention of U12-type introns of MAPK9 and MAPK14 leads to their reduced protein expression. Overall, our findings highlight that both ZRSR1 and ZRSR2 are functional components of the murine U12-spliceosome, and depletion of both proteins is required to model accurately ZRSR2-mutant MDS in mice.
2022-03-09 | GSE152432 | GEO
Project description:Recurrent loss-of-function mutations of spliceosome gene, ZRSR2, occur in myelodysplastic syndromes (MDS). Mutation/loss of ZRSR2 in human myeloid cells primarily causes impaired splicing of the U12-type introns. To investigate further the role of this splice factor in splicing and hematopoietic development, we generated mice lacking ZRSR2. Unexpectedly, Zrsr2-deficient mice developed normal hematopoiesis with no abnormalities in myeloid differentiation evident in either young or ≥1-year old knockout mice. Repopulation ability of Zrsr2-deficient hematopoietic stem cells was also unaffected in reconstitution assays. Myeloid progenitors lacking ZRSR2 exhibited mis-splicing of U12-type introns, however, this phenotype was moderate compared to the ZRSR2-deficient human cells. Our investigations revealed that a closely related homolog, Zrsr1, expressed in the murine hematopoietic cells, but not human, contributes to splicing of U12-type introns. Depletion of Zrsr1 in Zrsr2 KO myeloid cells exacerbated retention of the U12-type introns, thus highlighting a collective role of ZRSR1 and ZRSR2 in murine U12-spliceosome. We also demonstrate that aberrant retention of U12-type introns of MAPK9 and MAPK14 leads to their reduced protein expression. Overall, our findings highlight that both ZRSR1 and ZRSR2 are functional components of the murine U12-spliceosome, and depletion of both proteins is required to model accurately ZRSR2-mutant MDS in mice.
2022-03-09 | GSE151470 | GEO
Project description:Recurrent loss-of-function mutations of spliceosome gene, ZRSR2, occur in myelodysplastic syndromes (MDS). Mutation/loss of ZRSR2 in human myeloid cells primarily causes impaired splicing of the U12-type introns. To investigate further the role of this splice factor in splicing and hematopoietic development, we generated mice lacking ZRSR2. Unexpectedly, Zrsr2-deficient mice developed normal hematopoiesis with no abnormalities in myeloid differentiation evident in either young or ≥1-year old knockout mice. Repopulation ability of Zrsr2-deficient hematopoietic stem cells was also unaffected in reconstitution assays. Myeloid progenitors lacking ZRSR2 exhibited mis-splicing of U12-type introns, however, this phenotype was moderate compared to the ZRSR2-deficient human cells. Our investigations revealed that a closely related homolog, Zrsr1, expressed in the murine hematopoietic cells, but not human, contributes to splicing of U12-type introns. Depletion of Zrsr1 in Zrsr2 KO myeloid cells exacerbated retention of the U12-type introns, thus highlighting a collective role of ZRSR1 and ZRSR2 in murine U12-spliceosome. We also demonstrate that aberrant retention of U12-type introns of MAPK9 and MAPK14 leads to their reduced protein expression. Overall, our findings highlight that both ZRSR1 and ZRSR2 are functional components of the murine U12-spliceosome, and depletion of both proteins is required to model accurately ZRSR2-mutant MDS in mice.
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Project description:To determine the global impact of the clbn mutation on gene expression and efficiency of U2- and U12-type splicing, we analyzed the transcriptome of 108hpf wt and clbn mutant larvae by microarrays and RNA sequencing. RNAseq data was used to characterize intron retention of U2-type and U12-type intron on a genome-wide scale to confirm that rnpc3 deficiency specifically impairs U12-type splicing. RNAseq and microarray data were combined to yield high-confidence lists of differentially expressed genes which show that impaired U12-type splicing has a wide-ranging effect on the developing transcriptome. Total RNA was prepared from pools consisting of approx. 20 individually genotyped homozygous wildtype or mutant larvae, respectively. Three biologically independent replicate pools were generated and analyzed for each condition.
2014-02-05 | E-GEOD-53934 | biostudies-arrayexpress
Project description:To determine the global impact of the clbn mutation on gene expression and efficiency of U2- and U12-type splicing, we analyzed the transcriptome of 108hpf wt and clbn mutant larvae by microarrays and RNA sequencing. RNAseq data was used to characterize intron retention of U2-type and U12-type intron on a genome-wide scale to confirm that rnpc3 deficiency specifically impairs U12-type splicing. RNAseq and microarray data were combined to yield high-confidence lists of differentially expressed genes which show that impaired U12-type splicing has a wide-ranging effect on the developing transcriptome. RNAseq libraries prepared from 108 hours post-fertilization zebrafish larvae (approx. 60 embryos each, genotyped homozygous wildtype and homozygous clbns841 mutants, respectively)
2014-02-05 | E-GEOD-53758 | biostudies-arrayexpress
Project description:To determine the global impact of the clbn mutation on gene expression and efficiency of U2- and U12-type splicing, we analyzed the transcriptome of 108hpf wt and clbn mutant larvae by microarrays and RNA sequencing. RNAseq data was used to characterize intron retention of U2-type and U12-type intron on a genome-wide scale to confirm that rnpc3 deficiency specifically impairs U12-type splicing. RNAseq and microarray data were combined to yield high-confidence lists of differentially expressed genes which show that impaired U12-type splicing has a wide-ranging effect on the developing transcriptome.
2014-02-05 | GSE53934 | GEO
Project description:To determine the global impact of the clbn mutation on gene expression and efficiency of U2- and U12-type splicing, we analyzed the transcriptome of 108hpf wt and clbn mutant larvae by microarrays and RNA sequencing. RNAseq data was used to characterize intron retention of U2-type and U12-type intron on a genome-wide scale to confirm that rnpc3 deficiency specifically impairs U12-type splicing. RNAseq and microarray data were combined to yield high-confidence lists of differentially expressed genes which show that impaired U12-type splicing has a wide-ranging effect on the developing transcriptome.
2014-02-05 | GSE53758 | GEO
Project description:Mutant mice with respect to the splicing factor Zrsr1 present altered spermatogenesis and infertility. To investigate whether Zrsr1 is involved in the homeostatic control that the hypothalamus exerts over reproductive functions, we first analyzed both differential gene and isoform expression and alternative splicing alterations in Zrsr1 mutant (Zrsr1mu) hypothalamus; second, we analyzed the spontaneous and social behavior of Zrsr1mu mice; and third, we analyzed adult cell proliferation and survival in the Zrsr1mu hypothalamus. The Zrsr1mu hypothalamus showed altered expression of genes and isoforms related to the glutathione metabolic process, synaptonemal complex assembly, mRNA transport, and altered splicing events involving the enrichment of U12-type intron retention (IR). Furthermore, increased IR in U12-containing genes related with the prolactin, progesterone, and gonadotropin-releasing hormone (GnRH) reproductive signaling pathway was observed. This was associated with a hyperactive phenotype in both males and females, with an anxious phenotype in females, and with increased social interaction in males, instead of the classical aggressive behavior. In addition, Zrsr1mu females but not males exhibited reduced cell proliferation in both the hypothalamus and the subventricular zone. Overall, these results suggest that Zrsr1 expression and function are relevant to organization of the hypothalamic cell network controlling behavior.
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Project description:We identify RBM41 as a novel unique protein component of the minor spliceosome. RBM41 has no previously recognized cellular function but has been identified as a paralog of the U11/U12-65K protein, a known unique component of the minor spliceosome that functions during the early steps of minor intron recognition as a component of the U11/U12 di-snRNP. We show that both proteins use their highly similar C-terminal RRMs to bind to 3'-terminal stem-loops in U12 and U6atac snRNAs with comparable affinity. Our BioID data indicate that the unique N-terminal domain of RBM41 is necessary for its association with complexes containing DHX8, an RNA helicase, which in the major spliceosome drives the release of mature mRNA from the spliceosome. Consistently, we show that RBM41 associates with excised U12-type intron lariats, is present in the U12 mono-snRNP, and is enriched in Cajal bodies, together suggesting that RBM41 functions in the post-splicing steps of the minor spliceosome assembly/disassembly cycle. This contrasts with the U11/U12-65K protein, which uses the N-terminal region to interact with U11 snRNP during the intron recognition step. Finally, we show that while RBM41 knockout cells are viable, they show alterations in the splicing of U12-type introns, particularly differential U12-type 3' splice site usage. Together, our results highlight the role 3’-terminal stem-loop of U12 snRNA as a dynamic binding platform for the paralogous U11/U12-65K and RBM41 proteins, which function at distinct stages of minor spliceosome assembly/disassembly cycle.
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