Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MBD5 and MBD6 couple DNA methylation to gene silencing through the J-domain protein SILENZIO

ABSTRACT: DNA methylation is associated with transcriptional repression of eukaryotic genes and transposons, but the downstream mechanism of gene silencing is largely unknown. Here we describe two Arabidopsis methyl-CpG binding domain proteins, MBD5 and MBD6, that are recruited to chromatin by recognition of CG methylation, and redundantly repress a subset of genes and transposons without affecting DNA methylation levels. These methyl-readers recruit a J-domain protein, SILENZIO, that acts as a transcriptional repressor in loss-of-function and gain-of-function experiments. J-domain proteins often serve as co-chaperones with HSP70s. Indeed, we found that SILENZIO?s conserved J-domain motif was required for its interaction with HSP70s and for its silencing function. These results uncover an unprecedented role of a molecular chaperone J-domain protein in gene silencing downstream of DNA methylation.

ORGANISM(S): Arabidopsis thaliana Lambdavirus lambda

PROVIDER: GSE165095 | GEO | 2021/06/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

MBD5 and MBD6 couple DNA methylation to gene silencing through the J-domain protein SILENZIO

Project description:MBD5 and MBD6 couple DNA methylation to gene silencing through the J-domain protein SILENZIO

| PRJNA693252 | ENA

ACD15, ACD21 and SLN regulate accumulation and mobility of MBD6 to silence genes and transposable elements [ChIP-seq]

Project description:DNA methylation mediates silencing of transposable elements and genes in part via recruitment of the Arabidopsis MBD5/6 complex, which contains the methyl-CpG-binding domain (MBD) proteins MBD5 and MBD6, and the J-domain containing protein SILENZIO (SLN). Here we characterize two additional complex members: α-crystalline domain containing proteins ACD15 and ACD21. We show that they are necessary for gene silencing, bridge SLN to the complex, and promote higher order multimerization of MBD5/6 complexes within heterochromatin. These complexes are also highly dynamic, with the mobility of complex components regulated by the activity of SLN. Using a dCas9 system, we demonstrate that tethering the ACDs to an ectopic site outside of heterochromatin can drive massive accumulation of MBD5/6 complexes into large nuclear bodies. These results demonstrate that ACD15 and ACD21 are critical components of gene silencing complexes that act to drive the formation of higher order, dynamic assemblies.

2023-09-14 | GSE234531 | GEO

ACD15, ACD21 and SLN regulate accumulation and mobility of MBD6 to silence genes and transposable elements [RNA-seq]

2023-09-14 | GSE234530 | GEO

Single-nucleus RNA-seq reveals that MBD5, MBD6, and SILENZIO maintain silencing in the vegetative cell of developing pollen

Project description:Silencing of transposable elements (TEs) drove the evolution of numerous redundant mechanisms of transcriptional regulation. Arabidopsis MBD5, MBD6, and SILENZIO act as TE repressors downstream of DNA methylation. Here we show via single-nucleus RNA-seq of developing male gametophytes that these repressors are critical for TE silencing in the pollen vegetative cell, which undergoes epigenetic reprogramming causing chromatin decompaction to support fertilization by sperm cells. Instead, other silencing mutants (met1, ddm1, mom1, morc) show loss of silencing in all pollen nucleus types and somatic cells. We found that TEs repressed by MBD5/6 gain accessibility in wild-type vegetative nuclei despite remaining silent, suggesting that loss of DNA compaction makes them sensitive to loss of MBD5/6. Consistently, crossing mbd5/6 to histone 1 mutants, which have decondensed chromatin in leaves, reveals derepression of MBD5/6-dependent TEs in leaves. MBD5/6 and SILENZIO thus act as a silencing system especially important when chromatin compaction is compromised.

2022-10-27 | GSE202422 | GEO

MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer

Project description:The BRCA1-associated protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase (UCH), which forms a multi-protein complex with different epigenetic factors such as ASXL1-3, and FOXK1/2. At chromatin, BAP1 catalyzes the removal of mono-ubiquitination on histone H2AK119 in collaboration with other subunits within the complex, and therefore functions as a transcriptional activator. However, the crosstalk between different subunits and how these subunits impact BAP1 function remains unclear. Here, we report the identification of the methyl-CpG-binding domain proteins 5 and 6 (MBD5 and MBD6) that bind to the C-terminal PHD fingers of the large scaffold subunits ASXL1-3 and stabilize the BAP1 complex at chromatin. We further identified a previously uncharacterized Drosophila protein, the six-banded (SBA), as the ortholog of human MBD5/6. We demonstrated the core module of the BAP1 complex is structurally and functionally conserved during the evolution from Drosophila (Calypso/ASX/SBA) to human cells (BAP1/ASXL/MBD). Dysfunction of the BAP1 complex induced by the misregulation/mutations in each subunit is frequent in human cancer. In BAP1-dependent human cancers, MBD6 tends to be a dominant form. Depletion of MBD6 leads to a global loss of BAP1 occupancy at chromatin, resulting in a reduction of BAP1-dependent gene expression and tumor growth in vitro and in vivo. In summary, our study has uncovered MBD5/6 as important regulators of the BAP1 complex and transcription, and sheds light on the therapeutic potential of targeting MBD5/6 in human cancer.

2022-09-15 | GSE196860 | GEO

MBD5, a m5C RNA reader, regulates histone ubiquitylation in development and function

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

MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription [RNA-Seq]

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

MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription [ChIP-Seq]

2023-02-16 | GSE225100 | GEO

MBD5 and MBD6 couple DNA methylation to gene silencing through the J-domain protein SILENZIO.

Project description:DNA methylation is associated with transcriptional repression of eukaryotic genes and transposons, but the downstream mechanism of gene silencing is largely unknown. Here we describe two Arabidopsis methyl-CpG binding domain proteins, MBD5 and MBD6, that are recruited to chromatin by recognition of CG methylation, and redundantly repress a subset of genes and transposons without affecting DNA methylation levels. These methyl-readers recruit a J-domain protein, SILENZIO, that acts as a transcriptional repressor in loss-of-function and gain-of-function experiments. J-domain proteins often serve as co-chaperones with HSP70s. Indeed, we found that SILENZIO's conserved J-domain motif was required for its interaction with HSP70s and for its silencing function. These results uncover an unprecedented role of a molecular chaperone J-domain protein in gene silencing downstream of DNA methylation.

| S-EPMC8639832 | biostudies-literature

Functional genomic consequences of MBD5 knockdown in mouse brain and CRISPR-derived neurons [mouse]

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data