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Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE63816 | GEO | 2015/01/15

SECONDARY ACCESSION(S): PRJNA269142

REPOSITORIES: GEO

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Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome

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.

2015-01-15 | E-GEOD-63816 | biostudies-arrayexpress

ZRSR1 cooperates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells

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

ZRSR1 cooperates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells II

2023-05-29 | GSE151471 | GEO

ZRSR1 cooperates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells I

2022-03-09 | GSE151470 | GEO

Global analysis of binding sites of U2AF1 and ZRSR2 reveals RNA elements required for mutually exclusive splicing by the U2- and U12-type spliceosome

Project description:Eukaryotic nuclear introns have been dichotomously classified into common U2-type introns and rare U12-type introns. Because the highly conserved consensus sequences for the 5’ splice site and the branch point are found within all U12-type introns, weighted matrices for these motifs are used for prediction of U12-type introns. However, the U12-type consensus sequences per se are also recognized by the U2-type spliceosome. To better understand how distinct splicing systems recognize their authentic splice sites, we determined the binding sites of splicing factors, U2AF1 and ZRSR2, and found that ZRSR2 binding is mostly limited to U12-type introns. Our results reveal RNA elements contributing to selection of U2-type and U12-type splice sites in a mutually exclusive manner.

2022-05-24 | GSE203531 | GEO

Zrsr2 is essential for hematopoiesis and splicing of minor introns in RNA and protein processing genes in zebrafish

Project description:ZRSR2 is an essential splicing factor involved in 3’-splice site recognition as a component of both the major and minor spliceosomes that mediate splicing of U2- and U12-type introns, respectively. Transcriptome analysis of ZRSR2-mutated bone marrow samples and ZRSR2-knockdown cell lines has revealed its essential role in the minor spliceosome. We established a zrsr2-knockout zebrafish line, termed zrsr2hg129/hg129 (p.Trp167Argfs*9) using CRISPR/Cas9 technology. Global transcriptome analysis of 3 dpf zrsr2hg129/hg129 embryos revealed that loss of Zrsr2 leads to aberrant retention of minor introns in about one third of all minor intron-containing genes in zebrafish. Interestingly, these genes showed an enrichment for the RNA and protein processing pathways. Overall, our study has demonstrated that the role of Zrsr2 as a component of the minor spliceosome is conserved in zebrafish.

2022-09-28 | GSE193365 | GEO

Distinct functions for the paralogous RBM41 and U11/U12-65K proteins in the minor spliceosome

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.

2024-02-04 | GSE246283 | GEO

ZRSR1 cooperates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells

Project description:ZRSR1 cooperates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells

| PRJNA639332 | ENA

ZRSR1 cooperates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells I

Project description:ZRSR1 cooperates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells I

| PRJNA635920 | ENA

CRISPR-Cas9 knockdown of RBM48 in K562 cells

Project description:U12-type or minor (U12) introns are spliced by a distinct minor spliceosome and are found in the vast majority of multicellular eukaryotes, including plants and animals. Although U12 introns constitute less than 0.5% of all introns in many species, minor intron containing genes (MIGs) are important for organismal growth, development and pathology. We recently reported that maize RNA Binding Motif Protein 48 (RBM48) is required for U12-type intron splicing. Maize rbm48 mutants have genome-wide defects of U12 intron splicing, leading to abnormal endosperm cell differentiation and proliferation. To investigate whether RBM48 mediated U12 splicing is conserved between maize and humans, we generated a CRISPR/Cas9-mediated RBM48 functional knockout of the human RBM48 ortholog (RBM48 FunKO) in human K-562 cells.

2020-08-20 | GSE156471 | GEO

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