Loss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood

Sznajder, Łukasz J.; Scotti, Marina M.; Shin, Jihae; Taylor, Katarzyna; Ivankovic, Franjo; Nutter, Curtis A.; Aslam, Faaiq; Subramony, S. H.; Ranum, Laura P.W.; Swanson, Maurice S.

doi:10.1038/s41467-020-15962-x

Cited by 19 publications

(28 citation statements)

References 73 publications

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“…Among the top 20 most statistically significant DEGs were genes associated with these processes ( Fig. 4 C), for example, Mmp14 , a membrane-bound matrix metalloproteinase involved in breakdown of the extracellular matrix ( Kessenbrock et al, 2010 ); H1f0 , an H1 linker histone necessary for the condensation of nucleosome chains into higher-order chromatin structures, which is involved in the regulation of mRNA splice site recognition ( Kalashnikova et al, 2013 ; Di Liegro et al, 2018 ); and Mbnl1 , a regulator of alternative splicing that functions in the control of T-cell development, and is overexpressed in mixed lineage leukaemia ( Ho et al, 2004 ; Wang et al, 2012 ; Sznajder et al, 2020 ; Itskovich et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…The GO analysis also showed enrichment for several terms related to RNA splicing, and for terms connected to cell matrix adhesion (Fig 4B). Amongst the top 20 most statistically significant DEG were genes associated with these processes (Fig 4C ): for example, Mmp14, a membrane bound matrix metalloproteinase involved in breakdown of the extracellular matrix(55); H1f0, an H1 linker histone necessary for the condensation of nucleosome chains into higher-order chromatin structures, which is involved in the regulation of mRNA splice site recognition (56,57); and Mbnl1, a regulator of alternative splicing, which functions in the control of T-cell development, and is over-expressed in mixed lineage leukemia (58)(59)(60)(61).…”

Section: Foxa1 and Foxa2 Regulate Exon Usagementioning

confidence: 99%

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The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection

et al. 2021

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During positive selection at the transition from CD4+CD8+ double-positive (DP) to single-positive (SP) thymocyte, TCR signalling results in appropriate MHC restriction and signals for survival and progression. We show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection of mouse T cells and that Foxa1 and Foxa2 have overlapping/compensatory roles. Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes reduced positive selection and development of CD4SP, CD8SP and peripheral naïve CD4+ T cells. Foxa1 and Foxa2 regulated the expression of many genes encoding splicing factors and regulators, including Mbnl1, H1f0, Sf3b1, Hnrnpa1, Rnpc3, Prpf4b, Prpf40b and Snrpd3. Within the positively selecting CD69+DP cells, alternative RNA splicing was dysregulated in the double Foxa1/Foxa2 conditional knockout, leading to >850 differentially used exons. Many genes important for this stage of T-cell development (Ikzf1-3, Ptprc, Stat5a, Stat5b, Cd28, Tcf7) and splicing factors (Hnrnpab, Hnrnpa2b1, Hnrnpu, Hnrnpul1, Prpf8) showed multiple differentially used exons. Thus, Foxa1 and Foxa2 are required during positive selection to regulate alternative splicing of genes essential for T-cell development, and, by also regulating splicing of splicing factors, they exert widespread control of alternative splicing.

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Section: Resultsmentioning

confidence: 99%

Section: Foxa1 and Foxa2 Regulate Exon Usagementioning

confidence: 99%

The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection

et al. 2021

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“…For example, the SF SF3B3 is upregulated and contributes to tumorigenesis by regulating EZH2 pre-mRNA splicing, representing a key prognostic factor and therapeutic target in clear cell renal cell carcinoma (19). Similarly, many recent studies have shown that DASEs regulated by differentially expressed SFs have effects on tumorigenesis, the epithelial-mesenchymal transition, and lymphatic metastasis (12,(20)(21)(22)(23)(24). Therefore, analyses of DASEs can be meaningful in an oncogenic context.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Analyses of Prognostic and Therapeutic Alternative Splicing Signatures in Bladder Urothelial Carcinoma

et al. 2021

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BackgroundAlternative splicing (AS) is an indispensable post-transcriptional modification applied during the maturation of mRNA, and AS defects have been associated with many cancers. This study was designed to thoroughly analyze AS events in bladder urothelial carcinoma (BLCA) at the genome-wide level.MethodsWe adopted a gap analysis to screen for significant differential AS events (DASEs) associated with BLCA. DASEs with prognostic value for OS and the disease-free interval (DFI) were identified by Cox analysis. In addition, a differential AS network and AS clusters were identified using unsupervised cluster analysis. We examined differences in the sensitivity to chemotherapy and immunotherapy between BLCA patients with high and low overall survival (OS) risk.ResultsAn extensive number of DASEs (296) were found to be clinically relevant in BLCA. A prognosis model was established based prognostic value of OS and DFI. CUGBP elav-like family member 2 (CELF2) was identified as a hub splicing factor for AS networks. We also identified AS clusters associated with OS using unsupervised cluster analysis, and we predicted that the effects of cisplatin and gemcitabine chemotherapy would be different between high- and low-risk groups based on OS prognosis.ConclusionWe completed a comprehensive analysis of AS events in BLCA at the genome-wide level. The present findings revealed that DASEs and splicing factors tended to impact BLCA patient survival and sensitivity to chemotherapy drugs, which may provide novel prospects for BLCA therapies.

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“…RNA-seq con rmed the regulation of MBNL1 on the cell apoptosis signaling pathway. Some research have pointed out that MBNL1 may play an important role in the cell apoptosis (Wu et al, 2018;Sznajder et al, 2020). They pointed out that MBNL1 overexpression signi cantly decreased the proliferation rate and increased apoptosis (Wu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia (Itskovich et al, 2020). And loss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood (Sznajder et al, 2020). Repression of MBNL1-dependent alternative splicing may contribute to the regulation of stem cell fates (Welte et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

MBNL1 Regulates the Expression and Alternative Splicing of Genes Enriched in Cell Adhesion and Apoptosis

Liu

Song

et al. 2021

Preprint

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Muscleblind Like Splicing Regulator 1 (MBNL1), one canonical RNA binding protein (RBP), plays important roles in the regulation of the alternative splicing (AS) on pre-mRNAs. MBNL1 has traditionally been considered involved in the pathogenesis of myotonic dystrophy. Recent researches point out that MBNL1 has an effect on cancer progress, but the underlying mechanisms are unclear. In this study, we obtained the regulated transcriptome profile of MBNL1 in HeLa cells by RNA-seq analysis. The results showed that the knockdown of MBNL1 promoted cell proliferation while inhibited apoptosis. We found 398 genes were differentially up-regulated and 277 down-regulated by MBNL1 knockdown (KD). The differentially expressed genes (DEGs) regulated by MBNL1-KD were enriched in the signal pathways of homophilic cell adhesion, apoptotic process, extracellular matrix organization and cell migration. Systematical AS analysis revealed 504 MBNL1-regulated AS events. The regulated alternative splicing genes (RASGs) were enriched in the signal pathways of apoptotic signaling pathway, positive regulation of apoptotic process, adherent junction, fatty acid elongation and DNA repair. In summary, our results demonstrate that the knockdown of MBNL1 have significant effects on cell proliferation and apoptosis by regulating the expression and alternative splicing of associated genes, illustrating the possible molecular mechanisms of MBNL1 in cancer pathogenesis and progression and other diseases.

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Loss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood

Cited by 19 publications

References 73 publications

The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection

The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection

Genome-Wide Analyses of Prognostic and Therapeutic Alternative Splicing Signatures in Bladder Urothelial Carcinoma

MBNL1 Regulates the Expression and Alternative Splicing of Genes Enriched in Cell Adhesion and Apoptosis

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