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The RNA hairpin binder TRIM71 modulates alternative splicing by repressing MBNL1

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE134125 | GEO | 2019/08/01

REPOSITORIES: GEO

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The RNA hairpin binder TRIM71 modulates alternative splicing by repressing MBNL1.

Project description:TRIM71/LIN-41, a phylogenetically conserved regulator of development, controls stem cell fates. Mammalian TRIM71 exhibits both RNA-binding and protein ubiquitylation activities, but the functional contribution of either activity and relevant primary targets remain poorly understood. Here, we demonstrate that TRIM71 shapes the transcriptome of mouse embryonic stem cells (mESCs) predominantly through its RNA-binding activity. We reveal that TRIM71 binds targets through 3' untranslated region (UTR) hairpin motifs and that it acts predominantly by target degradation. TRIM71 mutations implicated in etiogenesis of human congenital hydrocephalus impair target silencing. We identify a set of primary targets consistently regulated in various human and mouse cell lines, including MBNL1 (Muscleblind-like protein 1). MBNL1 promotes cell differentiation through regulation of alternative splicing, and we demonstrate that TRIM71 promotes embryonic splicing patterns through MBNL1 repression. Hence, repression of MBNL1-dependent alternative splicing may contribute to TRIM71's function in regulating stem cell fates.

| S-EPMC6719626 | biostudies-literature

The RNA hairpin binder TRIM71 modulates alternative splicing by repressing Mbnl1

Project description:We demonstrate that global effects of TRIM71 on the cellular transcriptome of mouse embryonic stem cells (mESCs) are largely attributable to its RNA binding activity, and map the transcriptome-wide targets of wild-type TRIM71, NHL domain mutant TRIM71, and RING domain mutant TRIM71.

2019-08-01 | GSE130248 | GEO

The RNA hairpin binder TRIM71 modulates alternative splicing by repressing Mbnl1 [RNA-seq]

Project description:We demonstrate that TRIM71 alters stem cell splicing patterns through modulation of MBNL1 levels.

2019-08-01 | GSE130897 | GEO

The RNA hairpin binder TRIM71 modulates alternative splicing by repressing Mbnl1 [RNA-seq & Ribo-seq]

Project description:We demonstrate that global effects of TRIM71 on the cellular transcriptome of mouse embryonic stem cells (mESCs) are largely attributable to its RNA binding activity. We observe that target repression by TRIM71 in mESCs occurs predominantly through transcript degradation. We identify a core set of targets consistently regulated by TRIM71 in different human and mouse cell lines.

2019-08-01 | GSE130898 | GEO

The RNA hairpin binder TRIM71 modulates alternative splicing by repressing MBNL1

Project description:The RNA hairpin binder TRIM71 modulates alternative splicing by repressing MBNL1

| PRJNA554208 | ENA

The RNA hairpin binder TRIM71 modulates alternative splicing by repressing Mbnl1

Project description:The RNA hairpin binder TRIM71 modulates alternative splicing by repressing Mbnl1

| PRJNA534452 | ENA

The RNA hairpin binder TRIM71 modulates alternative splicing by repressing Mbnl1 [RNA-seq]

Project description:The RNA hairpin binder TRIM71 modulates alternative splicing by repressing Mbnl1 [RNA-seq]

| PRJNA541923 | ENA

The RNA hairpin binder TRIM71 modulates alternative splicing by repressing Mbnl1 [RNA-seq & Ribo-seq]

Project description:The RNA hairpin binder TRIM71 modulates alternative splicing by repressing Mbnl1 [RNA-seq & Ribo-seq]

| PRJNA541924 | ENA

MBNL1 alternative splicing isoforms play opposing roles in cancer.

Project description:The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 ?ex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 ?ex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.

| S-EPMC6238595 | biostudies-literature

Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-08-13 | E-GEOD-47678 | biostudies-arrayexpress