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Knockout mice reveal an essential role for Epithelial splicing regulatory proteins (Esrps) in mammalian development and epithelial splicing in vivo

ABSTRACT: Tissue- and cell-type specific regulators of alternative splicing (AS) are an essential layer of posttranscriptional gene regulation necessary for normal cellular function, patterning, and development. Here we report the Epithelial splicing regulatory proteins (Esrps) are required for patterning of multiple organs, with loss of both paralogs, Esrp1 and Esrp2, resulting in increasingly severe phenotypes. Global profiling of the Esrp splicing regulatory network from total epidermis revealed varied splicing sensitivity of Esrp targets upon loss of Esrp1 or double knockout. This may explain the progressive phenotypes seen in Esrp knockout mice, and these mice provide a unique genetic tool to evaluate functional consequences of epithelial splicing events in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE64357 | GEO | 2015/09/08

SECONDARY ACCESSION(S): PRJNA270823

REPOSITORIES: GEO

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Knockout mice reveal an essential role for Epithelial splicing regulatory proteins (Esrps) in mammalian development and epithelial splicing in vivo

Project description:Tissue- and cell-type specific regulators of alternative splicing (AS) are an essential layer of posttranscriptional gene regulation necessary for normal cellular function, patterning, and development. Here we report the Epithelial splicing regulatory proteins (Esrps) are required for patterning of multiple organs, with loss of both paralogs, Esrp1 and Esrp2, resulting in increasingly severe phenotypes. Global profiling of the Esrp splicing regulatory network from total epidermis revealed varied splicing sensitivity of Esrp targets upon loss of Esrp1 or double knockout. This may explain the progressive phenotypes seen in Esrp knockout mice, and these mice provide a unique genetic tool to evaluate functional consequences of epithelial splicing events in vivo. RNA from purified total epidermis (basal keratinocyte layer to cornified layer) of E18.5 mouse embryos were harvested by Trizol extraction. (Esrp1+/+, Esrp2-/- (n=2), Esrp1-/-, Esrp2+/+ (n=3), Esrp1-/-, Esrp2+/- (n=2), and Esrp1-/-, Esrp2-/- (n=2). 1 ug of total RNA was used for for RNA-seq library preparation using the TruSeq™ Stranded mRNA LT Sample Prep Kit (Illumina). 100x2 bp paired-end RNA-seq reads were generated on a HiSeq 2000 sequencer.

2015-09-08 | E-GEOD-64357 | biostudies-arrayexpress

The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate alternative splicing events

Project description:Epithelial Splicing Regulatory Proteins 1 and 2 (ESRP1 and ESRP2) are recently discovered epithelial-specific RNA-binding proteins that promote splicing of the epithelial variant of the FGFR2, ENAH, CD44, and CTNND1 transcripts. To catalogue a larger set of splicing events under the regulation of the ESRPs, we profiled splicing changes induced by RNA interference-mediated knockdown of ESRP1 and ESRP2 expression in a human epithelial cell line using the splicing-sensitive Affymetrix Exon ST1.0 Arrays. Analysis of the microarray data using the previously described MADS tool resulted in the identification of over a hundred candidate ESRP-regulated splicing events. We were able to independently validate 37 of these targets by RT-PCR. The ESRP-regulated events encompass all known types of alternative splicing events. Importantly, a number of these regulated splicing events occur in gene transcripts that encode proteins with well-described roles in the regulation of actin cytoskeleton organization, cell-cell adhesion, cell polarity, and cell migration. In sum, this work reveals a novel list of transcripts differentially spliced in epithelial and mesenchymal cells, implying that coordinated alternative splicing plays a critical role in determination of cell type identity. Keywords: control / knockdown comparison Short interfering knockdown of ESRP1 and ESRP2 in human PNT2 prostatic epithelium cells was performed as described before (Warzecha et al., 2009, Molecular Cell 33:591-601). The efficiency of ESRP1 and ESRP2 knockdown was monitored by quantitative RT-PCR as described before (Warzecha et al., 2009, Molecular Cell 33:591-601). In all cases the efficiency of the knockdown was close to 80%. We conducted Exon array profiling on RNAs from four siESRP1/2-treated samples and four siGFP controls.

2010-08-18 | E-GEOD-17468 | biostudies-arrayexpress

The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate alternative splicing events

2009-08-15 | GSE17468 | GEO

Ablation of the epithelial-specific splicing factor Esrp1 results in ureteric branching defects and reduced nephron number

Project description:Evaluation of splicing in ureteric epithelium in Esrp1;Esrp2 double knockout mice compared to Esrp1+/+;Esrp2-/- control mice.

2016-05-21 | GSE81716 | GEO

An ESRP-regulated splicing program is abrogated during the Epithelial Mesenchymal Transition

Project description:Alternative splicing achieves coordinated changes in post-transcriptional gene expression programs through the activities of diverse RNA binding proteins. Epithelial Splicing Regulatory Proteins 1 and 2 (ESRP1 and ESRP2) are cell type-specific regulators of transcripts that switch splicing during the Epithelial Mesenchymal Transition (EMT). To define a comprehensive program of alternative splicing that is regulated during the EMT, we identified an extensive ESRP-regulated splicing network of hundreds of alternative splicing events within numerous genes with roles in cell-cell adhesion, polarity, and migration. Loss of this global ESRP-regulated epithelial splicing program induces the phenotypic changes in cell morphology that are observed during the EMT. Components of this splicing signature provide novel molecular markers that can be used to characterize the EMT. Bioinformatics and experimental approaches revealed a high affinity ESRP binding motif and a predictive RNA map that governs their activity. This work establishes the ESRPs as coordinators of a complex alternative splicing network that adds an important post-transcriptional layer to the changes in gene expression that underlie epithelial-mesenchymal transitions during development and disease. Keywords: control / knockdown comparison and control / ectopic expression comparison

2010-08-23 | GSE22937 | GEO

Determination of a comprehensive alternative splicing regulatory network and the combinatorial regulation by key factors during Epithelial-to-Mesenchymal Transition [ESRP KD]

Project description:Epithelial specific splicing regulatory protein 1 and 2 (ESRP1 and ESRP2) are important regulators of alternative splicing during EMT. To study the alternative splicing events regulated by ESRP1/2 at a genome wide scale, we used lentiviral shRNAs to knockdown ESRP1/2 in H358 cells and performed RNA-seq in biological triplicates. We used lentiviral based shRNAs targeting ESRP1 and ESRP2 to knockdown both regulators in human H358 cells. We harvested total RNA and protein from ESRP1/2 knockdown and control knockdown in biological triplicates. We made cDNA libraries for each replicate and subjected them to RNA-seq.

2016-04-05 | E-GEOD-75489 | biostudies-arrayexpress

A regulatory axis between Epithelial Splicing Regulatory Proteins and Estrogen Receptor alpha modulates the alternative transcriptome of luminal breast cancer

Project description:The epithelial splicing regulatory proteins 1 and 2 (ESRP1/2) control the epithelial‐to‐mesenchymal transition (EMT) splicing program in cancer. However, their exact role in Breast Cancer (BC) remains under debate. Here, we report that ESRP1, but not ESRP2, is overexpressed in luminal BCs patients with poor prognosis and correlates with Estrogen Receptor α (ERα) mRNA levels. Analysis of ERα genome binding profiles in both cell lines and primary breast tumors showed its binding on both ESRP1 and ESRP2 promoters, and the expression of these genes strongly decreased by ERα silencing in hormone-deprived conditions (apoERα). The combined knock down of ESRP1/2 in MCF-7 cells followed by RNA-Seq, revealed the dysregulation of 754 genes expression, with a widespread alteration of alternative splicing events (ASEs) of genes involved in cell signaling, metabolism, cell growth, and EMT. Functional network analysis of ASEs that correlate with ESRP1/2 expression in ERα+ BCs showed RAC1 as the hub node in the protein-protein interactions altered by ESRP1/2 silencing. The comparison of apoERα- and ESRP-modulated ASEs revealed 63 commonly regulated events, including 27 detected both in primary BCs and endocrine resistant cell lines. Our data support a functional implication of the ERα-ESRP1/2 axis in the onset and progression of BC by controlling the splicing patterns of related genes.

2022-06-20 | GSE206474 | GEO

Multiphasic and dynamic changes in alternative splicing during induction of pluripotency are coordinated by numerous RNA binding proteins [ESRP DKO]

Project description:Alternative splicing (AS) plays a critical role in cell fate transitions, development and disease. Recent studies have shown that AS also influences pluripotency and somatic cell reprogramming. We profiled transcriptome-wide AS changes that occur during reprogramming of fibroblasts to pluripotency. This analysis revealed distinct phases of AS during reprogramming, including a splicing program that is unique to transgene-independent iPS cells. Changes in the expression of alternative splicing factors Zcchc24, Esrp1, Mbnl1/2 and Rbm47 were demonstrated to be key contributors to phase-specific AS. RNA binding motif enrichment analysis near alternatively spliced exons provided further insight into the combinatorial regulation of AS during reprogramming by different RNA binding proteins. Ectopic expression of Esrp1 enhanced reprogramming, in part by modulating the AS of the epithelial specific transcription factor Grhl1.These data represent a comprehensive temporal analysis of the dynamic regulation of AS during the acquisition of pluripotency. ES cells from 3 independent E3.5 blastocysts from either Control (Esrp1 WT/WT; Esrp2 -/-) or Esrp DKO (Esrp1 floxed/floxed; Esrp2 -/-) were transfected with pLVX-EGFP-Cre, puro selected and RNA was isolated 6 days later.

2016-03-15 | E-GEOD-76222 | biostudies-arrayexpress

Determination of a comprehensive alternative splicing regulatory network and the combinatorial regulation by key factors during Epithelial-to-Mesenchymal Transition [ESRP KD]

2016-04-05 | GSE75489 | GEO

Transcriptomic Analysis of PNN- and ESRP1-regulation in Human Corneal Epithelial Cells

Project description:Pnn depletion in developing mouse corneal epithelium led to disrupted alternative splicing of multiple ESRP-regulated epithelial-type exons. In human corneal epithelial cells (HCET), ESRP1 and PNN displayed close localization in and around nuclear speckles and their physical association in protein complexes was identified. In this study, gene expression profiling was performed to identify PNN- and ESRP1-regulated alternative pre-mRNA splicing in human corneal epithelial cells. Immortalized human corneal epithelial cells harboring doxycycline-inducible shRNA against PNN or ESRP1 were created. Whole transcriptome array analysis on ESRP1 or PNN knockdown HCET cells revealed clear alterations in transcript level and splicing pattern of specific subsets of genes with significant overlaps in their candidate targets. Our data suggest that ESRP1 and PNN modulate alternative splicing of a specific subset of exons, but not general splicing events. ESRP1 and PNN may together participate in the regulation of epithelial-specific splicing program in a genome-wide fashion. Parental HCET, shRNA-PNN HCET, and shRNA-ESRP1 HCET cells were cultured for 3 days with/without doxycycline. Total RNA was isolated from four biological replicates of each sample group and then subjected to hGlue3_0 transcriptome array analysis.

2013-01-24 | E-GEOD-41996 | biostudies-arrayexpress

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