Genome-wide analysis of gene expression and intron retention during development in a U12-type splicing-deficient zebrafish mutant
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ABSTRACT:
PROVIDER: PRJNA236230 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1104968.fastq.gz | Fastqsanger.gz | |||
| SRR1104969.fastq.gz | Fastqsanger.gz |
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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)
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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.
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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.
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Project description:Somatic mutations in the spliceosome gene ZRSR2 (located on the X chromosome) are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3' splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here, we characterize ZRSR2 as an essential component of the minor spliceosome (U12-dependent) assembly. shRNA mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns, and RNA-Sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns while splicing of the U2-type introns remain mostly unaffected. ZRSR2 deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS. RNA sequencing was performed on 16 bone marrow samples (MDS and normal) and six samples of control or ZRSR2 shRNA transduced TF-1 cells and data was analysed for aberrant splicing caused by ZRSR2 mutations/deficiency.
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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: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: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:Somatic mutations in the spliceosome gene ZRSR2— located on the X chromosome — are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3΄ splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here, we characterize ZRSR2 as an essential component of the minor spliceosome (U12-dependent) assembly. shRNA mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns, and RNA-Sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns while splicing of the U2-type introns remain mostly unaffected. ZRSR2 deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS.
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