MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription [RNA-Seq]
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ABSTRACT:
PROVIDER: PRJNA934468 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23421862_1.fastq.gz | Fastqsanger.gz | |||
| SRR23421862_2.fastq.gz | Fastqsanger.gz | |||
| SRR23421863_1.fastq.gz | Fastqsanger.gz | |||
| SRR23421863_2.fastq.gz | Fastqsanger.gz | |||
| SRR23421864_1.fastq.gz | Fastqsanger.gz |
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Project description:MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription
| PRJNA933923 | ENA
Project description:MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription [ChIP-Seq]
| PRJNA934463 | ENA
Project description:Epilepsy is considered to result from an imbalance between excitation and inhibition of the central nervous system. Pathogenic mutations in the methyl-CpG binding domain protein 5 gene (MBD5) are known to cause epilepsy. However, the function and mechanism of MBD5 in epilepsy remain elusive. Here, we found that MBD5 was mainly localized in the pyramidal cells and granular cells of mouse hippocampus, and its expression was increased in the brain tissues of mouse models of epilepsy. Exogenous overexpression of MBD5 inhibited the transcription of the signal transducer and activator of transcription 1 gene (Stat1), resulting in increased expression of N-methyl-D-aspartate receptor (NMDAR) subunit 1 (GluN1), 2A (GluN2A) and 2B (GluN2B), leading to aggravation of the epileptic behaviour phenotype in mice. In contrast, overexpression of STAT1 reduced the expression of NMDARs and alleviated the epileptic behavioural phenotype of mice. Furthermore, the epileptic behavioural phenotype was relieved by the NMDAR antagonist memantine. These results indicate that MBD5 accumulation affects seizures through STAT1-mediated inhibition of NMDAR expression in mice. Collectively, our findings suggest that the MBD5-STAT1- NMDAR pathway may be a new pathway that regulates the epileptic behavioural phenotype and may represent a new treatment target.
2023-02-16 | GSE225101 | GEO
Project description:Epilepsy is considered to result from an imbalance between excitation and inhibition of the central nervous system. Pathogenic mutations in the methyl-CpG binding domain protein 5 gene (MBD5) are known to cause epilepsy. However, the function and mechanism of MBD5 in epilepsy remain elusive. Here, we found that MBD5 was mainly localized in the pyramidal cells and granular cells of mouse hippocampus, and its expression was increased in the brain tissues of mouse models of epilepsy. Exogenous overexpression of MBD5 inhibited the transcription of the signal transducer and activator of transcription 1 gene (Stat1), resulting in increased expression of N-methyl-D-aspartate receptor (NMDAR) subunit 1 (GluN1), 2A (GluN2A) and 2B (GluN2B), leading to aggravation of the epileptic behaviour phenotype in mice. In contrast, overexpression of STAT1 reduced the expression of NMDARs and alleviated the epileptic behavioural phenotype of mice. Furthermore, the epileptic behavioural phenotype was relieved by the NMDAR antagonist memantine. These results indicate that MBD5 accumulation affects seizures through STAT1-mediated inhibition of NMDAR expression in mice. Collectively, our findings suggest that the MBD5-STAT1- NMDAR pathway may be a new pathway that regulates the epileptic behavioural phenotype and may represent a new treatment target.
2023-02-16 | GSE225100 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-02-16 | GSE225102 | GEO
Project description:MBD5 can physically interact with BAP1. Some genes may be regulated by both MBD5 and BAP1. We used microarrays to check whether the overlaps of differentially expressed genes when knockdown MBD5 or BAP1 were more than that would be expected by chance. Thus, we could suggest that BAP1 was required for the regulatory effect of MBD5
2018-03-15 | GSE111817 | GEO
Project description:Background: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. Methods: In an effort to gain insight into the complex interactions associated with genetic alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of the heterozygous hypomorphic Mbd5+/GT mouse model and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. Results: Gene expression analyses of three brain regions from Mbd5+/GT mice showed cortex as the region most affected by the knockdown, indicating context-dependent effects. Gene co-expression network analyses revealed gene clusters that are associated with MBD5 knockdown and enriched for GPCR signaling and terms related to ciliary function. We also identified genes that were downregulated in both models such as EPHA3, OLIG1, related to neuronal development and glial function. Limitations: These analyses were performed in a limited number of brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across brain tissues during early brain developmentneurodevelopment in ASD. Conclusions: Our study points to transcriptional consequences of Mbd5 disruption in the brain and suggests a link between MBD5 and pathways such as ciliary function that are associated with established developmental disorders and syndromes.
2020-01-28 | GSE144277 | GEO
Project description:Background: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. Methods: In an effort to gain insight into the complex interactions associated with genetic alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of the heterozygous hypomorphic Mbd5+/GT mouse model and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. Results: Gene expression analyses of three brain regions from Mbd5+/GT mice showed cortex as the region most affected by the knockdown, indicating context-dependent effects. Gene co-expression network analyses revealed gene clusters that are associated with MBD5 knockdown and enriched for GPCR signaling and terms related to ciliary function. We also identified genes that were downregulated in both models such as EPHA3, OLIG1, related to neuronal development and glial function. Limitations: These analyses were performed in a limited number of brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across brain tissues during early brain developmentneurodevelopment in ASD. Conclusions: Our study points to transcriptional consequences of Mbd5 disruption in the brain and suggests a link between MBD5 and pathways such as ciliary function that are associated with established developmental disorders and syndromes.
2020-01-28 | GSE144279 | GEO
Project description:Methyl-CpG-binding domain (MBD)-containing proteins are readers of epigenetic information. The founding member, MeCP2, mutated in the Rett Syndrome, binds to methylated CpG DNAs. MBD5 is an evolutionarily conserved MBD family member associated with epilepsy, autism spectrum disorders (ASD), and early onset dementia. The mechanism of action of MBD5 remains unclear. Here we report that mbd5 regulates embryonic development, erythrocyte differentiation, iron metabolism, and behavior in zebrafish. MBD5 is essential to activate the expression of erythrocyte differentiation genes (e.g., hbae3), iron-regulated genes (e.g., fth1), and ASD-related genes (e.g., gabbr2), by binding to 5-methylcytosine (m5C) modified mRNAs, interacting with and stabilizing Additional Sex Combs Like 1 (ASXL1), a component of the Polycomb Repressive Deubiquinase (PR-DUB) complex, to facilitate removal of the repressive monoubiquitin mark at histone H2A (H2A-K119Ub), thereby facilitating gene activation. Together, these findings reveal MBD5 as a m5C RNA reader that links RNA methylation to histone modification in vivo.
2024-05-15 | GSE222803 | GEO
Project description:Elevated c-Jun levels result in apoptosis and are evident in neurodegenerative disorders such as Alzheimer's disease and dementia and after global cerebral insults such as stroke and epilepsy. NMDA receptor (NMDAR) antagonists block c-Jun upregulation and prevent neuronal cell death following excitotoxic insults. However, little is known about the molecular mechanisms that regulate c-Jun abundance in neurons. Here we show that PRR7, a component of synaptic junctions, can upregulate c-Jun levels by inhibiting its ubiquitination in neurons. PRR7 interacts with the GLUN1 subunit of NMDARs and is upregulated in the nucleus following NMDAR activation. We show that PRR7 interacts with the E3 ligase SCFFBW7 (FBW7) and blocks the FBW7-mediated ubiquitination of c-Jun. PRR7 overexpression increases c-Jun-dependent transcriptional activity and promotes neuronal death. Microarray assays indicate that both Prr7 knockdown or overexpression alter the abundance of c-Jun-regulated transcripts associated with cellular viability as well as synaptic function. Moreover, Prr7 knockdown attenuates NMDA-mediated excitotoxicity in primary neuronal cultures. Our results show that PRR7 links NMDAR activity to c-Jun function and provide insight into the processes that underlie NMDA-dependent excitotoxicity. Four biological replicas of each of the four conditions: NO = not transduced with virus; NT = transduced with control lentiviruses containing a non-targeting shRNA sequence; KD = transduced with lentiviruses expressing PRR7-specific shRNAs; OE= transduced with lentiviruses to overexpress PRR7.
2014-10-25 | E-GEOD-62686 | biostudies-arrayexpress