Seizure-induced LIN28A disrupts pattern separation via aberrant hippocampal neurogenesis
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PROVIDER: PRJNA1033558 | ENA |
REPOSITORIES: ENA
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Project description:Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of pilocarpine-induced status epilepticus (SE), we characterized spatiotemporal expression of Lin28a mRNA and proteins after SE. Unlike Lin28a transcripts, induction of LIN28A protein after SE was detected mainly in the subgranular zone, where immunoreactivity was found in progenitors, neuroblasts, and immature and mature granule neurons. To investigate roles of LIN28A in epilepsy, we generated Nestin-Cre::Lin28aloxP/loxP (cKO) and Nestin-Cre::Lin28a+/+ (WT) mice to block LIN28A upregulation in all neuronal lineages after acute seizure. Adult-generated neuron- and hippocampus-associated cognitive impairments were absent in epileptic LIN28A cKO mice as evaluated by pattern separation and contextual fear conditioning tests, respectively, while sham-manipulated WT and cKO animals showed comparable memory function. Moreover, numbers of hilar PROX1-expressing ectopic granule cells (EGCs), together with PROX1/NEUN+ mature EGCs, were significantly reduced in epileptic cKO mice. Transcriptomic analysis and immunohistochemical validation at 3 d post-pilocarpine provided potential LIN28A downstream targets such as serotonin receptor 4. Collectively, our findings indicate that LIN28A is a novel target for regulation of newborn neuron-associated memory dysfunction in epilepsy by modulating seizure-induced aberrant neurogenesis.
2024-01-01 | GSE246519 | GEO
Project description:Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of pilocarpine-induced status epilepticus (SE), we characterized spatiotemporal expression of Lin28a mRNA and proteins after SE. Unlike Lin28a transcripts, induction of LIN28A protein after SE was detected mainly in the subgranular zone, where immunoreactivity was found in progenitors, neuroblasts, and immature and mature granule neurons. To investigate roles of LIN28A in epilepsy, we generated Nestin-Cre:Lin28aloxP/loxP (conditional KO [cKO]) and Nestin-Cre:Lin28a+/+ (WT) mice to block LIN28A upregulation in all neuronal lineages after acute seizure. Adult-generated neuron- and hippocampus-associated cognitive impairments were absent in epileptic LIN28A-cKO mice, as evaluated by pattern separation and contextual fear conditioning tests, respectively, while sham-manipulated WT and cKO animals showed comparable memory function. Moreover, numbers of hilar PROX1-expressing ectopic granule cells (EGCs), together with PROX1+/NEUN+ mature EGCs, were significantly reduced in epileptic cKO mice. Transcriptomics analysis and IHC validation at 3 days after pilocarpine administration provided potential LIN28A downstream targets such as serotonin receptor 4. Collectively, our findings indicate that LIN28A is a potentially novel target for regulation of newborn neuron-associated memory dysfunction in epilepsy by modulating seizure-induced aberrant neurogenesis.
| S-EPMC10906464 | biostudies-literature
Project description:We report the upregulated genes by the expression of LIN28A or loss of function mutant of LIN28A for 293FTcells..
2023-01-11 | GSE174387 | GEO
Project description:We report the direct target genes by LIN28A or loss of function mutant of LIN28A for 293FTcells using CLIP-Seq
2023-01-11 | GSE174388 | GEO
Project description:A developmentally regulated RNA binding protein, LIN28A and its homolog LIN28B may share a similar mechanism to regulate the processing of let-7 microRNAs (miRNAs) in embryonic stem cells (ESCs) or certain cancer cells, although their predominant localization is different in cells. However, little is known about the regulatory mechanism of LIN28A for miRNA processing in the nucleus. Here, we show that SET7/9, a known histone methyltransferase, associates with LIN28A in vivo and in vitro. SET7/9-mediated methylation significantly leads to the nuclear retention and protein stability of LIN28A, and remarkably regulated RNA binding ability of LIN28A to pri-let-7. Using RNAi knockdown approach, we find that the methylated nuclear form of LIN28A may function in the nucleoli by sequestering the primary let-7 miRNA to block their processing through a Tut4 (Zcchc11)-independent mechanism to regulate human ESC pluripotency. We propose a new insight toward the understanding of the molecular mechanism for post-translational methylation of nuclear LIN28A along modulating pluripotency by regulating pri-let-7 miRNAs in human ESCs.
2016-12-05 | GSE53038 | GEO
Project description:Lin28, a well-known RNA-binding protein, regulates diverse cellular properties. All physiological functions of Lin28A characterized so far have been attributed to its repression of let-7 miRNA biogenesis or modulation of the mRNA translational efficiency. Here we show that Lin28A directly binds to a consensus DNA sequence in vitro and in mouse embryonic stem cells in vivo. ChIP-seq and RNA-seq reveal the enrichment of Lin28A binding around transcription start sites, and a positive correlation between its genomic occupancy and expression of many associated genes. Mechanistically, Lin28A recruits 5-methylcytosine-dioxygenase Tet1 to genomic binding sites to orchestrate 5-methylcytosine and 5-hydroxymethylcytosine dynamics. Either Lin28A or Tet1 knockdown leads to dysregulated DNA methylation and expression of common target genes. These results reveal a surprising role for Lin28A in transcriptional regulation via epigenetic DNA modifications and provide a new framework for understanding mechanisms underlying versatile functions of Lin28A in mammalian systems. Examine the DNA binding ability of Lin28 and its roles in regulating gene expression by coordinating with Tet1
2015-12-07 | E-GEOD-74254 | biostudies-arrayexpress
Project description:The RNA-binding proteins Lin28A and Lin28B play critical roles in regulating gene expression through distinct mechanisms, including the inhibition of Let-7 microRNA maturation and direct mRNA binding. Predominantly expressed in pluripotent and multipotent stem cells, Lin28A and Lin28B contribute to a variety of biological processes such as development, growth, and tissue regeneration. Dysregulation of Lin28A/B expression is associated with numerous types of tumors. In this study, we demonstrate that overexpression of Lin28A in the mouse nephrons leads to severe inflammation and kidney damage, rather than to tumorigenesis. To investigate the causal relationship between kidney damage and inflammation, we utilized steroid treatment to suppress inflammation. This treatment also ameliorated the kidney damage phenotype, indicating that Lin28A overexpression directly induces inflammation, which in turn leads to kidney damage. Notably, Lin28A overexpression causes inflammation only when expressed in nephrons, but not in the stromal cells of the kidneys, highlighting its cell context-dependent nature. The nephron-specific, Lin28A-induced inflammatory response is distinct from the previously described Lin28B-mediated inflammatory feedback loops, as it is not IL-6 dependent. Instead, it is associated with the rapid upregulation of cytokines such as CXCL1 and CCL2. Overall, this study reveals that the impact of abnormal Lin28A expression is broader than previously understood, demonstrating that Lin28A overexpression also plays a role in inflammatory responses. Furthermore, this transgenic mouse model offers a valuable tool for advancing our understanding of the pathophysiology of acute kidney injury (AKI), where inflammation is a key factor.
2024-07-16 | GSE254805 | GEO
Project description:LIN28A is a highly-conserved RNA-binding protein which is known to be involved in embryonic development, stem cell maintenance and proliferation. LIN28A is expressed in various types of cancer, and they are associated with advanced tumor malignancy. In embryonic stem cell, LIN28A specifically binds to let-7 precursors to suppress biogenesis of the let-7 microRNA family. In addition, LIN28A was reported to bind several mRNAs such as Oct4, cyclin A/B and histone H2A to activate their translation. For comprehensive understanding of the interaction between LIN28A and their target RNAs, we exploited UV-crosslinking and immunoprecipitation (CLIP) to capture their in vivo binding to target RNAs. LIN28A-binding RNAs were identified in a mouse embryonic stem cell line using multiple monoclonal and polyclonal antibodies. The result shows that LIN28 preferentially binds to let-7 precursors through GGAG binding motif, which is consistent with our previous results. We also identified that LIN28A binding is enriched in a certain subset of mRNAs. To understand the function of the novel LIN28A-mRNA binding, we carried out ribosome profiling from LIN28A-depleted mouse embryonic stem cells. Examination of miRNA level in embryonic stem cell treated with siRNA for GFP or for Lin28a
2012-10-25 | E-GEOD-37112 | biostudies-arrayexpress
Project description:LIN28A is a highly-conserved RNA-binding protein which is known to be involved in embryonic development, stem cell maintenance and proliferation. LIN28A is expressed in various types of cancer, and they are associated with advanced tumor malignancy. In embryonic stem cell, LIN28A specifically binds to let-7 precursors to suppress biogenesis of the let-7 microRNA family. In addition, Lin28 was reported to bind several mRNAs such as Oct4, cyclin A/B and histone H2A to activate their translation. For comprehensive understanding of the interaction between LIN28A and their target RNAs, we exploited UV-crosslinking and immunoprecipitation (CLIP) to capture their in vivo binding to target RNAs. LIN28A-binding RNAs were identified in a mouse embryonic stem cell line using multiple monoclonal and polyclonal antibodies. The result shows that LIN28A preferentially binds to let-7 precursors through GGAG binding motif, which is consistent with our previous results. We also identified that LIN28A binding is enriched in a certain subset of mRNAs. To understand the function of the novel LIN28A-mRNA binding, we carried out ribosome profiling from LIN28A-depleted mouse embryonic stem cells. Examination of RNA binding of LIN28A and translation in mouse embryonic stem cell.
2012-10-25 | E-GEOD-37111 | biostudies-arrayexpress
Project description:LIN28A is a highly-conserved RNA-binding protein which is known to be involved in embryonic development, stem cell maintenance and proliferation. LIN28A is expressed in various types of cancer, and they are associated with advanced tumor malignancy. In embryonic stem cell, LIN28A specifically binds to let-7 precursors to suppress biogenesis of the let-7 microRNA family. In addition, LIN28A was reported to bind several mRNAs such as Oct4, cyclin A/B and histone H2A to activate their translation. For comprehensive understanding of the interaction between LIN28A and their target RNAs, we exploited UV-crosslinking and immunoprecipitation (CLIP) to capture their in vivo binding to target RNAs. LIN28A-binding RNAs were identified in a mouse embryonic stem cell line using multiple monoclonal and polyclonal antibodies. The result shows that LIN28 preferentially binds to let-7 precursors through GGAG binding motif, which is consistent with our previous results. We also identified that LIN28A binding is enriched in a certain subset of mRNAs. To understand the function of the novel LIN28A-mRNA binding, we carried out ribosome profiling from LIN28A-depleted mouse embryonic stem cells. Examination of mRNA level in embryonic stem cell treated with siRNA for GFP or for Lin28a
2012-10-25 | E-GEOD-37113 | biostudies-arrayexpress