Autism-like phenotype and risk gene-RNA deadenylation by CPEB4 mis-splicing
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ABSTRACT:
PROVIDER: PRJNA454216 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.
| S-EPMC6217926 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-03-06 | GSE113842 | GEO
Project description:Erythropoiesis is essential to mammals and is regulated at multiple steps by both extracellular and intracellular factors. Many transcriptional regulatory networks in erythroid differentiation have been well characterized. However, our understanding of post-transcriptional regulatory circuitries in this developmental process is still limited. Using genomic approaches, we identified a sequence-specific RNA-binding protein, Cpeb4, which is dramatically induced in terminal erythroid differentiation (TED) by two erythroid important transcription factors, Gata1/Tal1. Cpeb4 belongs to the cytoplasmic polyadenylation element binding (CPEB) protein family that regulates translation of target mRNAs in early embryonic development, neuronal synapse, and cancer. Using primary mouse fetal liver erythroblasts, we found that Cpeb4 is required for terminal erythropoiesis by repressing the translation of a set of mRNAs highly expressed in progenitor cells. This translational repression occurs by the interaction with a general translational initiation factor, eIF3. Interestingly, Cpeb4 also binds its own mRNA and represses its translation, thus forming a negative regulatory circuitry to limit Cpeb4 protein level. This mechanism ensures that the translation repressor, Cpeb4, does not interfere with the translation of other mRNAs in differentiating erythroblasts. Our study characterized a translational regulatorycircuitry that controls TED and revealed that Cpeb4 is required for somatic cell differentiation. We used microarray to identify mRNAs associated with Cpeb4 in mouse fetal liver erythroblasts. Cpeb4 associated mRNAs were isolated from mouse fetal liver erythroblasts using anti-Cpeb4 antibody for immunoprecipitation followed by RNA extraction. Then Affymetrix microarrays were used to identify and quantify the mRNAs associated with Cpeb4.
2015-12-09 | E-GEOD-57004 | biostudies-arrayexpress
Project description:Mutations or decreased expression of RNA-binding proteins (mRBPs) can lead to cardiomyopathies in humans. Here we defined RBPs in healthy and diseased primary cardiomyocytes at a system-wide level by RNA Interactome Capture. This identified 67 novel cardiomyocyte specific RBPs including several contractile proteins. Furthermore, we identified Cytoplasmic polyadenylation element binding protein 4 (Cpeb4) as a dynamic mRBP in diseased cardiomyocytes, regulating cardiac growth both in vitro and in vivo. To study Cpeb4 in cardiomyocytes, we identified mRNAs bound to and regulated by Cpeb4. Cpeb4 regulates cardiac remodeling by differential expression of transcription factors. Among Cpeb4 target mRNAs, two Zinc finger transcription factors (Zeb1 and Zbtb20) were identified. We show that Cpeb4 regulates the translation of these mRNAs and that Cpeb4 depletion increases their expression. Thus, Cpeb4 emerges as critical regulator of cardiomyocyte function by differential binding of specific mRNAs in response to pathological growth stimulation.
2020-06-29 | GSE153409 | GEO
Project description:Poly(A) tails protect RNAs from degradation and deadenylation rates determine RNA stability. Deadenylation has mostly been investigated within the cytoplasm and the dynamics of poly(A) tail length after transcription are not well understood. Combining long-read sequencing with metabolic labeling and cell fractionations, we investigate deadenylation dynamics of newly synthesized poly(A) tails in vitro and in vivo. We report evidence for genome-wide synthesis of poly(A) tails longer than 200 nt which are enriched upon splicing inhibition. Metabolic labeling reveals rapid deadenylation of poly(A) tails within minutes after transcription. Fractionation experiments show that initial deadenylation is a nuclear process, and that different classes of transcripts, including long noncoding RNAs, have distinctive nuclear poly(A) tail lengths. Modelling deadenylation dynamics predicts that deadenylation in the nucleus is by an order of magnitude faster than in the cytoplasm. In summary, we suggest nuclear deadenylation as a novel regulatory layer which may determine stability and abundance before mRNAs reach the cytoplasm.
2023-01-07 | GSE188539 | GEO
Project description:The Cytoplasmic Polyadenylation Element Binding (CPEB)-family of RNA-binding proteins regulates pre-mRNA processing and translation of CPE-containing mRNAs in early embryonic development and synaptic activity. However, the specific functions of each CPEB in the adult organism are poorly understood. Here we show that CPEB4 is required to suppress high fat diet- and aging-induced endoplasmic reticulum (ER) stress, and its subsequent hepatic steatosis. Stress-activated expression of CPEB4 in the liver is controlled through a double layer of regulation. First, Cpeb4 is transcriptionally regulated by the circadian clock and then, its mRNA translation is regulated by the Unfolded Protein Response (UPR) through the upstream Open Reading Frames (uORFs) present in its 5’ UTR. Thus, CPEB4 is synthesized only upon ER-stress but the amplitude of the induction is circadian. In turn, CPEB4 activates a second wave of UPR-translation required to maintain ER and mitochondrial homeostasis. Our results suggest that combined transcriptional and translational regulation of CPEB4 generates a “circadian mediator”, which
coordinates the hepatic UPR activity with periods of high ER protein-folding demand preventing non-alcoholic fatty liver disease (NAFLD).
2017-01-16 | GSE81875 | GEO
Project description:The Cytoplasmic Polyadenylation Element Binding (CPEB)-family of RNA-binding proteins regulates pre-mRNA processing and translation of CPE-containing mRNAs in early embryonic development and synaptic activity. However, the specific functions of each CPEB in the adult organism are poorly understood. Here we show that CPEB4 is required to suppress high fat diet- and aging-induced endoplasmic reticulum (ER) stress, and its subsequent hepatic steatosis. Stress-activated expression of CPEB4 in the liver is controlled through a double layer of regulation. First, Cpeb4 is transcriptionally regulated by the circadian clock and then, its mRNA translation is regulated by the Unfolded Protein Response (UPR) through the upstream Open Reading Frames (uORFs) present in its 5’ UTR. Thus, CPEB4 is synthesized only upon ER-stress but the amplitude of the induction is circadian. In turn, CPEB4 activates a second wave of UPR-translation required to maintain ER and mitochondrial homeostasis. Our results suggest that combined transcriptional and translational regulation of CPEB4 generates a “circadian mediator”, which
coordinates the hepatic UPR activity with periods of high ER protein-folding demand preventing non-alcoholic fatty liver disease (NAFLD).
2017-01-16 | GSE81876 | GEO
Project description:Erythropoiesis is essential to mammals and is regulated at multiple steps by both extracellular and intracellular factors. Many transcriptional regulatory networks in erythroid differentiation have been well characterized. However, our understanding of post-transcriptional regulatory circuitries in this developmental process is still limited. Using genomic approaches, we identified a sequence-specific RNA-binding protein, Cpeb4, which is dramatically induced in terminal erythroid differentiation (TED) by two erythroid important transcription factors, Gata1/Tal1. Cpeb4 belongs to the cytoplasmic polyadenylation element binding (CPEB) protein family that regulates translation of target mRNAs in early embryonic development, neuronal synapse, and cancer. Using primary mouse fetal liver erythroblasts, we found that Cpeb4 is required for terminal erythropoiesis by repressing the translation of a set of mRNAs highly expressed in progenitor cells. This translational repression occurs by the interaction with a general translational initiation factor, eIF3. Interestingly, Cpeb4 also binds its own mRNA and represses its translation, thus forming a negative regulatory circuitry to limit Cpeb4 protein level. This mechanism ensures that the translation repressor, Cpeb4, does not interfere with the translation of other mRNAs in differentiating erythroblasts. Our study characterized a translational regulatorycircuitry that controls TED and revealed that Cpeb4 is required for somatic cell differentiation. We used microarray to identify mRNAs associated with Cpeb4 in mouse fetal liver erythroblasts.
2015-12-09 | GSE57004 | GEO
Project description:To identify CPEB1 and CPEB4 regulated RNA we performed CPEB1 and CPEB4 RNA immunoprecipitation (RIP) followed by microarray hybridization analysis with striatal (St) RNA from wild-type (WT) and R6/1 mice (HD mice).
2020-03-06 | GSE113833 | GEO
Project description:CPEB4 prevents hepatic steatosis
| PRJNA322835 | ENA