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Systematic exploration of dynamic splicing networks reveals conserved multi-stage regulators of neurogenesis [SPARseq]

ABSTRACT: Alternative splicing (AS) is a critical regulatory layer, yet factors controlling networks of functionally coordinated splicing events during developmental transitions remain poorly understood. Here, we employ a multifaceted screening strategy to define factors that control dynamically regulated splicing events associated with neurogenesis. Among numerous previously unknown regulators, Rbm38 acts widely to negatively impact neural AS through Ptbp1-dependent and -independent mechanisms. Puf60, a ubiquitous splicing factor, is surprisingly found to promote neural splicing patterns. This activity is determined by a vertebrate-conserved, neural-differential exon that remodels Puf60 co-factor interactions. Ablation of this exon rewires distinct AS networks in embryonic stem cells and at multiple stages of neural Rbm38etc. Single-cell transcriptome analyses further reveal critical, multi-stage roles for Rbm38 and Puf60 isoforms in establishing neuronal identity. Our results thus reveal key new regulators of neurogenesis and establish how a single exon in a widely expressed splicing factor orchestrates temporal control over cell Rbm38etc.

ORGANISM(S): Mus musculus

PROVIDER: GSE186384 | GEO | 2022/07/15

REPOSITORIES: GEO

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Systematic exploration of dynamic splicing networks reveals conserved multi-stage regulators of neurogenesis [RNAseq_neuroDiff]

Project description:Alternative splicing (AS) is a critical regulatory layer, yet factors controlling networks of functionally coordinated splicing events during developmental transitions remain poorly understood. Here, we employ a multifaceted screening strategy to define factors that control dynamically regulated splicing events associated with neurogenesis. Among numerous previously unknown regulators, Rbm38 acts widely to negatively impact neural AS through Ptbp1-dependent and -independent mechanisms. Puf60, a ubiquitous splicing factor, is surprisingly found to promote neural splicing patterns. This activity is determined by a vertebrate-conserved, neural-differential exon that remodels Puf60 co-factor interactions. Ablation of this exon rewires distinct AS networks in embryonic stem cells and at multiple stages of neural differentiation. Single-cell transcriptome analyses further reveal critical, multi-stage roles for Rbm38 and Puf60 isoforms in establishing neuronal identity. Our results thus reveal key new regulators of neurogenesis and establish how a single exon in a widely expressed splicing factor orchestrates temporal control over cell differentiation.

2022-07-15 | GSE186388 | GEO

Systematic exploration of dynamic splicing networks reveals conserved multi-stage regulators of neurogenesis [RNAseq_Puf60]

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Systematic exploration of dynamic splicing networks reveals conserved multi-stage regulators of neurogenesis [RNAseq_N2Akd]

Project description:Alternative splicing (AS) is a critical regulatory layer, yet factors controlling networks of functionally coordinated splicing events during developmental transitions remain poorly understood. Here, we employ a multifaceted screening strategy to define factors that control dynamically regulated splicing events associated with neurogenesis. Among numerous previously unknown regulators, Rbm38 acts widely to negatively impact neural AS through Ptbp1-dependent and -independent mechanisms. Puf60, a ubiquitous splicing factor, is surprisingly found to promote neural splicing patterns. This activity is determined by a vertebrate-conserved, neural-differential exon that remodels Puf60 co-factor interactions. Ablation of this exon rewires distinct AS networks in embryonic stem cells and at multiple stages of neural Rbm38etc. Single-cell transcriptome analyses further reveal critical, multi-stage roles for Rbm38 and Puf60 isoforms in establishing neuronal identity. Our results thus reveal key new regulators of neurogenesis and establish how a single exon in a widely expressed splicing factor orchestrates temporal control over cell Rbm38etc.

2022-07-15 | GSE186386 | GEO

Systematic exploration of dynamic splicing networks reveals conserved multi-stage regulators of neurogenesis [CLIPseq]

Project description:Alternative splicing (AS) is a critical regulatory layer, yet factors controlling networks of functionally coordinated splicing events during developmental transitions remain poorly understood. Here, we employ a multifaceted screening strategy to define factors that control dynamically regulated splicing events associated with neurogenesis. Among numerous previously unknown regulators, Rbm38 acts widely to negatively impact neural AS through Ptbp1-dependent and -independent mechanisms. Puf60, a ubiquitous splicing factor, is surprisingly found to promote neural splicing patterns. This activity is determined by a vertebrate-conserved, neural-differential exon that remodels Puf60 co-factor interactions. Ablation of this exon rewires distinct AS networks in embryonic stem cells and at multiple stages of neural Rbm38etc. Single-cell transcriptome analyses further reveal critical, multi-stage roles for Rbm38 and Puf60 isoforms in establishing neuronal identity. Our results thus reveal key new regulators of neurogenesis and establish how a single exon in a widely expressed splicing factor orchestrates temporal control over cell Rbm38etc.

2022-07-15 | GSE186385 | GEO

The RNA binding protein RBM38 (RNPC1) regulates splicing during late erythroid differentiation

Project description:Alternative pre-mRNA splicing is a prevalent mechanism in mammals that promotes proteomic diversity, including expression of cell-type specific protein isoforms. We characterized a role for RBM38 (RNPC1) in regulation of alternative splicing during late erythroid differentiation. We used an affymetrix human exon junction (HJAY) splicing microarray to identify a panel of RBM38-regulated alternatively spliced transcripts. Using microarray databases, we noted high RBM38 expression levels in CD71+ erythroid cells and thus chose to examine RBM38 expression during erythroid differentiation of human hematopoietic stem cells, detecting enhanced RBM38 expression during late erythroid differentiation. In differentiated erythroid cells, we validated a subset of RBM38-regulated splicing events and determined that RBM38 regulates activation of Protein 4.1R (EPB41) exon 16 during late erythroid differentiation. Using Epb41 minigenes, Rbm38 was found to be a robust activator of exon 16 splicing. To further address the mechanism of RBM38-regulated alternative splicing, a novel mammalian protein expression system, followed by SELEX-Seq, was used to identify a GU-rich RBM38 binding motif. Lastly, using a tethering assay, we determined that RBM38 can directly activate splicing when recruited to a downstream intron. Together, our data support the role of RBM38 in regulating alternative splicing during erythroid differentiation. siRNA knockdown of RBM38 was perfomed in human MCF-7 breast cancer cells. The efficiency of RBM38 knockdown was monitored by western blot using an RBM38 antibody (Santa Cruz Biotechnology, SC-85873). We conducted HJAY exon and exon junction array profiling on RNAs from four siRBM38 treated MCF-7 samples vs. four sicontrol treated MCF-7 samples Control / knockdown comparison.

2013-07-29 | E-GEOD-49293 | biostudies-arrayexpress

The RNA binding protein RBM38 (RNPC1) regulates splicing during late erythroid differentiation

2013-07-29 | GSE49293 | GEO

RNA-Seq of 293T cells depleted of U2AF-related proteins

Project description:Characterization of RNA processing events dependent on U2AF-related proteins PUF60 and RBM39. PUF60 (poly-U-binding factor 60 kDa, also known as FIR, Hfp or Ro-bp1) is a splicing factor homologous to the 65 kD subunit of the auxiliary factor of U2 small nuclear ribonucleoprotein (U2AF65). PUF60 has two central RNA recognition motifs and a C-terminal U2AF homology motif (UHM), but lacks the N terminal arginine/serine-rich (RS) and UHM ligand motif (ULM) domains present in U2AF65. PUF60 activity, in conjunction with U2AF, facilitates the association of U2 snRNP with the pre-mRNA. PUF60 and U2AF65 can bind SF3b155 ULMs simultaneously and noncompetitively. RBM39 (also known as CAPERα, HCC1, FSAP59 or RNPC2) is an RNA processing factor and a hormone-dependent transcriptional coactivator. RBM39 domain structure is similar to PUF60, except for the extra N-terminal RS domain with unknown function. To understand function of the two proteins on a genome-wide scale, each protein was individually depleted from human embryonic kidney cell line 293 using RNAi to systematically characterize the PUF60- and RBM39-dependent exon usage.

2018-05-25 | E-MTAB-6010 | biostudies-arrayexpress

A global regulatory mechanism for activating an exon network required for neurogenesis

Project description:The vertebrate and neural-specific SR-related protein nSR100/SRRM4 regulates an extensive program of alternative splicing with critical roles in nervous system development. However, the mechanism by which nSR100 controls its target exons is poorly understood. We demonstrate that nSR100-dependent neural exons are associated with a unique configuration of intronic cis-elements that promote rapid switch-like regulation during neurogenesis. A key feature of this configuration is the insertion of specialized intronic enhancers between polypyrimidine tracts and acceptor sites that bind nSR100 to potently activate exon inclusion in neural cells, while weakening 3' splice site recognition and contributing to exon skipping in non-neural cells. nSR100 further operates by forming multiple interactions with early spliceosome components bound proximal to 3' splice sites. These multifaceted interactions achieve dominance over neural exon silencing mediated by the splicing regulator PTBP1. The results thus illuminate a widespread mechanism by which a critical neural exon network is activated during neurogenesis. RNA-Seq was used to obtain mRNA profiles of various N2A and 293T cell lines from human and mouse, respectively, to investigate the roles of nSR100, Ptbp1 and U2af65 in alternative splicing regulation. PAR-iCLIP and iCLIP experiments followed by high throughput sequencing were conducted to obtain RNA binding profiles of nSR100, PTBP1 and U2af65.

2014-09-11 | E-GEOD-57278 | biostudies-arrayexpress

A global regulatory mechanism for activating an exon network required for neurogenesis

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mRNAseq in control (WT) and Nes:Cre_Qk cKO

Project description:We sequenced mRNA from mouse E14.5 embryonic cortex to compare gene expression level and alternative splicing events between 2 control (WT) and 2 Qk cKO. A set of tissue specific splicing factors are thought to govern alternative splicing events during neural progenitors (NPC) to neuron transition by regulating neuron specific exons. Here we proposed one such a factor, RNA-binding protein Qki5, which is specifically expressed in neural stem cells. We performed mRNAseq analysis by using mRNAs obtained from developing cerebral cortices in Qk conditional knockout (cKO) mice. Expectedly, we found huge numbers of alternative splicing changes between control and conditional knock-out relative to that of transcripts level changes. Furthermore, DAVID and Meta-scape analysis revealed that affected spliced genes are involved in axon-development and microtubule-based process. Among these, Ninein protein coding mRNA is listed as a Qk protein dependent alternative splicing targets. Interestingly, this exon encodes very long poly-peptides (2,121 nt) and is known as a previously defined dynamic RNA switch during NPC-to-neuron transition. In addition, we validated that the regulation of this large exon is consistent with Qki5 dependent alternative exon inclusion mode obtained from our previous Qki5 HITS-CLIP analysis. Together Qki5 will add to a list factor of alternative splicing in NPC-to-neuron transition.

2019-04-17 | GSE123927 | GEO

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