MBD2 Ablation Impairs Lymphopoiesis and Impedes Progression and Maintenance of T-cell Acute Lymphoblastic Leukemia
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ABSTRACT:
PROVIDER: PRJNA415295 | ENA |
REPOSITORIES: ENA
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Project description:Little is known about the roles of methyl-CpG-binding domain protein 2 (MBD2), a “reader” of DNA methylation, in T-cell acute lymphoblastic leukemia (T-ALL). Here, we investigated the role of MBD2 in T-ALL by using an Mbd2 knockout mouse model. We found that MBD2 ablation impeded the progression and maintenance of Notch1-driven T-ALL.Our data reveals essential roles for MBD2 in lymphopoiesis and T-ALL and support an intriguing potential of MBD2 as a therapeutic target for T-ALL. To explore potential mechanisms underlying the anti-ALL effects of MBD2 ablation, leukemic cells were harvested from mice transplanted with WT or Mbd2-/- T-ALL cells, and their global gene expression profiles (GEP) were compared. Double positive (DP) thymocytes were isolated and used as a normal control.
2017-10-23 | GSE105763 | GEO
Project description:Transcriptional silencing of hypermethylated tumor suppressor genes is a hallmark of tumorigenesis, though the underlying mechanism remains enigmatic. In this study, we find Methyl-CpG-binding domain protein 2 (MBD2) forms nuclear condensate in diverse cancer cells, where it assembles and navigates the chromatin remodeler NuRD complex to these gene loci for transcriptional suppression, thus fueling tumor growth. Disturbance of MBD2 condensate reduces the level of NuRD complex-specific proteins, destabilizes heterochromatin foci, facilitates chromatin relaxation, and consequently impedes tumor progression. We demonstrate that MBD2 condensate is redox sensitive mediated by Cys359. Prooxidative interventions disperse MBD2-NuRD condensate, thereby alleviating the transcriptional repression of tumor suppressor genes. Our findings illuminate a hitherto unappreciated function of MBD2 condensate in sustaining a repressive chromatin state essential for cancer cell proliferation and suggest an oxidative stress targeting approach for malignancies with excessive MBD2 condensate.
2025-02-02 | GSE270303 | GEO
Project description:Transcriptional silencing of hypermethylated tumor suppressor genes is a hallmark of tumorigenesis, though the underlying mechanism remains enigmatic. In this study, we find Methyl-CpG-binding domain protein 2 (MBD2) forms nuclear condensate in diverse cancer cells, where it assembles and navigates the chromatin remodeler NuRD complex to these gene loci for transcriptional suppression, thus fueling tumor growth. Disturbance of MBD2 condensate reduces the level of NuRD complex-specific proteins, destabilizes heterochromatin foci, facilitates chromatin relaxation, and consequently impedes tumor progression. We demonstrate that MBD2 condensate is redox sensitive mediated by Cys359. Prooxidative interventions disperse MBD2-NuRD condensate, thereby alleviating the transcriptional repression of tumor suppressor genes. Our findings illuminate a hitherto unappreciated function of MBD2 condensate in sustaining a repressive chromatin state essential for cancer cell proliferation and suggest an oxidative stress targeting approach for malignancies with excessive MBD2 condensate.
2025-02-02 | GSE269469 | GEO
Project description:Transcriptional silencing of hypermethylated tumor suppressor genes is a hallmark of tumorigenesis, though the underlying mechanism remains enigmatic. In this study, we find Methyl-CpG-binding domain protein 2 (MBD2) forms nuclear condensate in diverse cancer cells, where it assembles and navigates the chromatin remodeler NuRD complex to these gene loci for transcriptional suppression, thus fueling tumor growth. Disturbance of MBD2 condensate reduces the level of NuRD complex-specific proteins, destabilizes heterochromatin foci, facilitates chromatin relaxation, and consequently impedes tumor progression. We demonstrate that MBD2 condensate is redox sensitive mediated by Cys359. Prooxidative interventions disperse MBD2-NuRD condensate, thereby alleviating the transcriptional repression of tumor suppressor genes. Our findings illuminate a hitherto unappreciated function of MBD2 condensate in sustaining a repressive chromatin state essential for cancer cell proliferation and suggest an oxidative stress targeting approach for malignancies with excessive MBD2 condensate.
2025-02-02 | GSE270305 | GEO
Project description:Transcriptional silencing of hypermethylated tumor suppressor genes is a hallmark of tumorigenesis, though the underlying mechanism remains enigmatic. In this study, we find Methyl-CpG-binding domain protein 2 (MBD2) forms nuclear condensate in diverse cancer cells, where it assembles and navigates the chromatin remodeler NuRD complex to these gene loci for transcriptional suppression, thus fueling tumor growth. Disturbance of MBD2 condensate reduces the level of NuRD complex-specific proteins, destabilizes heterochromatin foci, facilitates chromatin relaxation, and consequently impedes tumor progression. We demonstrate that MBD2 condensate is redox sensitive mediated by Cys359. Prooxidative interventions disperse MBD2-NuRD condensate, thereby alleviating the transcriptional repression of tumor suppressor genes. Our findings illuminate a hitherto unappreciated function of MBD2 condensate in sustaining a repressive chromatin state essential for cancer cell proliferation and suggest an oxidative stress targeting approach for malignancies with excessive MBD2 condensate.
2025-02-02 | GSE270304 | GEO
Project description:We show that in vivo MBD2 is mainly recruited to CpG island promoters that are highly methylated. We also report that MBD2 binds to a subset of CpG island promoters that are characterized by the presence of active histone marks and RNA polymerase II (Pol2). At such sites, MBD2 binds downstream of the transcription start site. Active promoters bound by MBD2 show low to medium gene expression levels and H3K36me3 deposition suggesting a putative role for MBD2 in blocking polymerase II (Pol2) elongation at these promoters.
2014-07-03 | GSE54693 | GEO
Project description:We show that in vivo MBD2 is mainly recruited to CpG island promoters that are highly methylated. We also report that MBD2 binds to a subset of CpG island promoters that are characterized by the presence of active histone marks and RNA polymerase II (Pol2). At such sites, MBD2 binds downstream of the transcription start site. Active promoters bound by MBD2 show low to medium gene expression levels and H3K36me3 deposition suggesting a putative role for MBD2 in blocking polymerase II (Pol2) elongation at these promoters. To gain further insight into the function of and epigenetic regulation by MBD2 we generated a tagged version of the protein and stably expressed it in the MCF-7 cell line. We mapped genome wide binding of MBD2 by ChIP sequencing (ChIP-seq) and together with base resolution whole genome bisulfite sequencing (WGBS) we were able to determine the methylation content and the role of methylation density at MBD2 enriched regions. We further dissected MBD2 binding properties, taking advantage of a large set of ChIP-seq data including active histone marks, RNA polymerase II (POL2) and strand specific RNA-seq.
2014-07-03 | E-GEOD-54693 | biostudies-arrayexpress
Project description:The heterogeneous collection of NuRD complexes can be grouped into the MBD2 or MBD3 containing complexes MBD2-NuRD and MBD3-NuRD. MBD2 is known to bind to methylated CpG sequences in vitro in contrast to MBD3. Although functional differences have been described, a direct comparison of MBD2 and MBD3 in respect to genome-wide binding and function has been lacking. Here we show when depleting cells for MBD2, the MBD2 bound genes increase their activity, whereas MBD2 plus MBD3 bound genes reduce their activity. Most strikingly, MBD3 is enriched at active promoters, whereas MBD2 is bound at methylated promoters and enriched at exon sequences of active genes. This suggests a functional connection between MBD2 binding to chromatin and splicing.
2013-02-08 | GSE41003 | GEO
Project description:Methylated DNA binding protein 2 (MBD2) has been shown to bind specific methylated promoters and suppress transcription. Here we systematically investigate MBD2 suppression by overexpressing MBD2 in MCF-10A cells and generating gene expression profiles of overexpressing cells and normal MCF-10A cells.
2013-06-17 | GSE47873 | GEO
Project description:The heterogeneous collection of NuRD complexes can be grouped into the MBD2 or MBD3 containing complexes MBD2-NuRD and MBD3-NuRD. Although functional differences have been described, a direct comparison of MBD2 and MBD3 in respect to genome-wide binding and function has been lacking. Here we show a strong enrichment for MBD2 at methylated CpG sequences, whereas CpGs bound by MBD3 are devoid of methylation. Gene activity of MBD2 bound genes is four fold lower as compared to genes bound by MBD3. When depleting cells for MBD2, the MBD2 bound genes increase their activity, whereas MBD2 plus MBD3 bound genes reduce their activity. Most strikingly, MBD3 is enriched at active promoters, whereas MBD2 is bound at methylated promoters and enriched at exon sequences of active genes. This suggests a functional connection between MBD2 binding to chromatin and splicing.
2013-02-08 | GSE41006 | GEO