Hippocampus-dependent learning and memory deficits by abnormalities in presynaptic plasticity in LSD1 knock-in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE94018 | GEO | 2017/08/31
SECONDARY ACCESSION(S): PRJNA363062
REPOSITORIES: GEO
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Project description:Lysine-specific demethylase 1 (LSD1) is a histone demethylase that participates in transcriptional repression or activation. Recent studies reported that LSD1 is involved in learning and memory. Although LSD1 phosphorylation by PKC? was implicated in circadian rhythmicity, the importance of LSD1 phosphorylation in learning and memory is unknown. In this study, we examined the roles of LSD1 in synaptic plasticity and memory using Lsd1 SA/SA knock-in (KI) mice, in which a PKC? phosphorylation site is mutated. Interestingly, short-term and long-term contextual fear memory as well as spatial memory were impaired in Lsd1 KI mice. In addition, short-term synaptic plasticity, such as paired pulse ratio and post-tetanic potentiation was impaired, whereas long-term synaptic plasticity, including long-term potentiation and long-term depression, was normal. Moreover, the frequency of miniature excitatory postsynaptic current was significantly increased, suggesting presynaptic dysfunction in Lsd1 KI mice. Consistent with this, RNA-seq analysis using the hippocampus of Lsd1 KI mice showed significant alterations in the expressions of presynaptic function-related genes. Intriguingly, LSD1n-SA mutant showed diminished binding to histone deacetylase 1 (HDAC1) compared to LSD1n-WT in SH-SY5Y cells. These results suggest that LSD1 is involved in the regulation of presynaptic gene expression and subsequently regulates the hippocampus-dependent memory in phosphorylation-dependent manner.
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Project description:To analyze the functional relevance of LSD1 in neuroblastic tumors, SH-SY5Y cells were transiently transfected with siRNA directed against LSD1 or with a scrambled control siRNA. Microarray analysis revealed changes in expression that were consistent with these observations 72 hours after LSD1 knock-down. At this time, 28 genes were significantly induced at least 1.5-fold and 29 genes were significantly repressed at least 1.5-fold. Among the 28 induced genes, 4 are markers of cytoskeletal remodelling (TNS1, TPM1, DNM2, DNAL4), indicating differentiation, and 3 (TPM1, DNM2 and SHANK2) are functionally linked to neurite dynamics and synaptic trafficking. TaqMan quantitative RT-PCR confirmed the expression changes detected via microarray analysis for LSD1, DNAL4, DNM2, TNS1 and TPM1
2008-10-22 | GSE13273 | GEO
Project description:To analyze the functional relevance of LSD1 in neuroblastic tumors, SH-SY5Y cells were transiently transfected with siRNA directed against LSD1 or with a scrambled control siRNA. Microarray analysis revealed changes in expression that were consistent with these observations 72 hours after LSD1 knock-down. At this time, 28 genes were significantly induced at least 1.5-fold and 29 genes were significantly repressed at least 1.5-fold. Among the 28 induced genes, 4 are markers of cytoskeletal remodelling (TNS1, TPM1, DNM2, DNAL4), indicating differentiation, and 3 (TPM1, DNM2 and SHANK2) are functionally linked to neurite dynamics and synaptic trafficking. TaqMan quantitative RT-PCR confirmed the expression changes detected via microarray analysis for LSD1, DNAL4, DNM2, TNS1 and TPM1 Experiment Overall Design: SH-SY5Y cells were transfected with siRNA directed against LSD1 or control siRNA. 2 independent transfection experiments were performed each. Reverse transcription, labelling of total RNA and subsequent hybridization to Affymetrix U133v2 chips were performed according to the manufacturer´s protocols
2008-11-13 | E-GEOD-13273 | biostudies-arrayexpress
Project description:Precise control of transcriptional programs underlying metazoan development is modulated by enzymatically active co-regulatory complexes, coupled with epigenetic strategies, but how specific members of histone modification enzyme families such as histone methyltransferases and demethylases are utilized in vivo to simultaneously orchestrate distinct developmental gene activation and repression programs remains unclear. Here, we report that the initially-described histone lysine demethylase, LSD1, a component of the CoREST/CtBP corepressor complex, is required for late cell-lineage determination and differentiation during pituitary organogenesis. Surprisingly, LSD1 acts primarily on target gene activation programs, as well as in gene repression programs, based on recruitment of distinct LSD1-containing coactivator or corepressor complexes. Intriguingly, LSD1-dependent gene repression programs can be extended late in development with the induced expression of ZEB1, a Kr.pple-like repressor that can act as a molecular beacon for recruitment of the LSD1-containing CtBP/CoREST corepressor complex, causing repression of an additional cohort of genes, such as GH, that previously required LSD1 for activation.
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Project description:Tumor-initiating cells (TICs) play a critical role in glioblastoma (GBM) maintenance being responsible for its heterogeneity and resistance to standard therapy. A step toward clinical translation includes GBM TIC targeting. Among the molecules tested for GBM treatment, are those targeting epigenetic modifiers. By using patient-derived TICs and xenograft orthotopic models, we identified Lysine-specific histone demethylase 1A (LSD1) as a potentially druggable target in GBM. LSD1-directed therapy by means of the selective, orally bioavailable and brain penetrant inhibitor DDP_38003 effectively impairs growth, stem-like features and tumorigenic potential of GBM TICs. Our findings point to LSD1 as a positive regulator of Activating Transcription Factor 4 (ATF4)-dependent response in all stress conditions arising during tumor growth and therapy. Thus, through the downregulation of either ATF4 and its adaptive genes, LSD1 targeting is likely a promising strategy to hit GBM TICs by counteracting the ATF4-mediated adaptation to stress.
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