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Conserved functional antagonism between CELF and MBNL proteins regulates stem cell-specific alternative splicing and regeneration in planarians

ABSTRACT: Understanding gene regulation in stem cells is key to understanding stem cell biology.Contrary to transcriptional regulation the function of alternative splicing (AS) in stem cells is poorly understood. Here we study function and mechanisms of AS in a powerful in vivo model for stem cell biology, the planarian S. mediterranea. Knockdown of AS factors, computational analyses of massive RNA-sequencing data, phenotyping, and biochemical binding assays revealed a stem cell specific AS program comprising hundreds of alternative exons, intron retention events, and microexons. The conserved AS factors CELF/MBNL are main regulators of this program. We show that they antagonize each other by directly promoting or repressing stem cell specific AS events. Knockdown of CELF/MBNL leads to defective regeneration by affecting self-renewal and differentiation, respectively. Thus, AS is of key importance for stem cell regulation in vivo and antagonistic regulation by CELF/MBNL is likely an ancestral feature of animal stem cells. Sequencing of polyA-selected RNA from Schmidtea mediterranea individuals after control, smed-bruno-like(RNAi) and mbnl(RNAi) after 20,25,30 days after RNAi

ORGANISM(S): Schmidtea mediterranea

SUBMITTER: Marta Rodriguez Orejuela

PROVIDER: E-GEOD-75296 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Conserved functional antagonism between CELF and MBNL proteins regulates stem cell-specific alternative splicing and regeneration in planarians

Project description:Understanding gene regulation in stem cells is key to understanding stem cell biology. Contrary to transcriptional regulation the function of alternative splicing (AS) in stem cells is poorly understood. Here we study function and mechanisms of AS in a powerful in vivo model for stem cell biology, the planarian S. mediterranea. Knockdown of AS factors, computational analyses of massive RNA-sequencing data, phenotyping, and biochemical binding assays revealed a stem cell specific AS program comprising hundreds of alternative exons, intron retention events, and microexons. The conserved AS factors CELF/MBNL are main regulators of this program. We show that they antagonize each other by directly promoting or repressing stem cell specific AS events. Knockdown of CELF/MBNL leads to defective regeneration by affecting self-renewal and differentiation, respectively. Thus, AS is of key importance for stem cell regulation in vivo and antagonistic regulation by CELF/MBNL is likely an ancestral feature of animal stem cells. mRNA profiles of various samples of planarian cells, including control and knockdowns of key splicing factors in whole worms, and FACS-purified fractions

2016-08-01 | E-GEOD-75594 | biostudies-arrayexpress

Conserved functional antagonism between CELF and MBNL proteins regulates stem cell-specific alternative splicing and regeneration in planarians (dataset 3)

2016-08-01 | GSE75594 | GEO

Conserved functional antagonism between CELF and MBNL proteins regulates stem cell-specific alternative splicing and regeneration in planarians (dataset 1)

Project description:Understanding gene regulation in stem cells is key to understanding stem cell biology.Contrary to transcriptional regulation the function of alternative splicing (AS) in stem cells is poorly understood. Here we study function and mechanisms of AS in a powerful in vivo model for stem cell biology, the planarian S. mediterranea. Knockdown of AS factors, computational analyses of massive RNA-sequencing data, phenotyping, and biochemical binding assays revealed a stem cell specific AS program comprising hundreds of alternative exons, intron retention events, and microexons. The conserved AS factors CELF/MBNL are main regulators of this program. We show that they antagonize each other by directly promoting or repressing stem cell specific AS events. Knockdown of CELF/MBNL leads to defective regeneration by affecting self-renewal and differentiation, respectively. Thus, AS is of key importance for stem cell regulation in vivo and antagonistic regulation by CELF/MBNL is likely an ancestral feature of animal stem cells.

2016-08-01 | GSE75296 | GEO

Muscleblind-like proteins regulate embryonic stem cell-specific alternative splicing and reprogramming I

Project description:Previous investigations of the core gene regulatory circuitry that controls embryonic stem cell (ESC) pluripotency have largely focused on the roles of transcription, chromatin and non- coding RNA regulators. Alternative splicing (AS) represents a widely acting mode of gene regulation, yet its role in the regulation of ESC pluripotency and differentiation is poorly understood. Here, we identify the Muscleblind-like RNA binding proteins, MBNL1 and MBNL2, as conserved and direct negative regulators of a large program of AS events that are differentially regulated between ESCs and other cell types. Knockdown of MBNL proteins in differentiated cells causes switching to an ESC-like AS pattern for at least half of these AS events. Among the events is an ESC-specific AS switch in the forkhead family transcription factor FOXP1 that controls pluripotency. Consistent with a central and negative regulatory role for MBNL proteins in pluripotency, their knockdown significantly enhances the expression of key pluripotency genes and the formation of induced pluripotent stem cells (iPSCs) during somatic cell reprogramming. mRNA profiles of various embryonic stem cells, tissues and cell lines from human and mouse using high-throughput sequencing data and the role of MBNL proteins in regulation of ESC-differential alternative splicing

2013-06-26 | E-GEOD-45503 | biostudies-arrayexpress

Muscleblind-like proteins regulate embryonic stem cell-specific alternative splicing and reprogramming II

2013-06-26 | E-GEOD-45504 | biostudies-arrayexpress

An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype.

Project description:Regulation of cell-cell junction formation and regulation of cell migration were enriched among EMT (Epithelial-Mesenchymal Transition)-associated alternatively splicing events. Our analysis suggested that most EMT-associated alternative splicing events are regulated by one or more members of the RBFOX, MBNL, CELF, hnRNP or ESRP classes of splicing factors. The EMT alternative splicing signature was confirmed in human breast cancer cell lines, which could be classified into basal and luminal subtypes based exclusively on their EMTassociated splicing pattern. Expression of EMT-associated alternative mRNA transcripts was also observed in primary breast cancer samples, indicating that EMT-dependent splicing changes occur commonly in human tumors. The functional significance of EMT-associated alternative splicing was tested by expression of the epithelial-specific splicing factor ESRP1 or depletion of RBFOX2 in mesenchymal cells, both of which elicited significant changes in cell morphology and motility towards an epithelial phenotype, suggesting that splicing regulation alone can drive critical aspects of EMT-associated phenotypic changes. The molecular description obtained here may aid in the development of new diagnostic and prognostic markers for analysis of breast cancer progression. Examination of transcriptomes of HMLE/Twist-ER before and after induction of EMT by tamoxifen

2011-07-15 | E-GEOD-30290 | biostudies-arrayexpress

Set1 and MLL1/2 target distinct sets of functionally different genomic loci in vivo: An in depth RNA-seq analysis of H3K4me3 targets in vivo and upon Set1 and mll1 knockdown

Project description:This study identifies expression differences upon knockdown of two H3K4 methyltransferases, Set1 and MLL1/2, in both the stem cells (X1) and whole worm (WW) tissue of the planarian flatworm Schmidtea mediterranea. To test this, we looked at the RNA-seq expression profile in WW and X1 tissue types upon RNAi knockdown of set1, mll1/2 and compared to a non-targeted RNAi control, unc22.

2015-12-17 | GSE74054 | GEO

Expression analyses of nanos(RNAi) and control(RNAi) Schmidtea mediterranea

Project description:Investigation of whole genome gene expression level changes in nanos(RNAi) Schmidtea mediterranea, compared to control animals. nanos(RNAi) animals are devoid of germ cells The samples analyzed in this study are further described in Wang, Y., Stary, JM., Wilhelm, JE. and Newmark, PA. 2010. A eight chip study using total RNA recovered from asexual nanos(RNAi), asexual control, juvenile sexual nanos(RNAi), and juvenile sexual control animals. Each chip measures the expression level of 16,797 ESTs from S. mediterranea with 10 60-mer probe pairs (PM/MM) per gene, with two-fold technical redundancy.

2010-09-01 | E-GEOD-22797 | biostudies-arrayexpress

An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype.

2011-07-15 | GSE30290 | GEO