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Harnessing of the Nucleosome Remodeling Deacetylase complex controls lymphocyte development and prevents leukemogenesis

ABSTRACT: Cell fate decisions depend on the interplay between chromatin regulators and transcription factors. Here we show that activity of the Mi-2u Nucleosome Remodeling and Deacetylase (NuRD) complex is controlled by the Ikaros family of lymphoid-lineage determining proteins. Ikaros, an integral component of the NuRD complex in lymphocytes, tethers this complex to active lymphoid differentiation genes, but keeps it in a functionally-poised state. Loss in Ikaros DNA binding activity causes a local increase in Mi-2u chromatin remodeling, histone deacetylation and suppression of lymphoid gene expression. The NuRD complex also redistributes to transcriptionally-poised non-Ikaros gene targets, involved in proliferation and metabolism, inducing their re-activation. Thus release of NuRD from Ikaros regulation blocks lymphocyte maturation and mediates progression to a leukemic state by engaging functionally-opposing epigenetic mechanisms and genetic networks. We used microarrays to detail the global programme of gene expression of mouse DP thymocyte after Ikaros inactivation with dominant negative of Ik at different stage.

ORGANISM(S): Mus musculus

PROVIDER: GSE32311 | GEO | 2011/11/13

SECONDARY ACCESSION(S): PRJNA147297

REPOSITORIES: GEO

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Harnessing of the Nucleosome Remodeling Deacetylase complex controls lymphocyte development and prevents leukemogenesis

Project description:Cell fate decisions depend on the interplay between chromatin regulators and transcription factors. Here we show that activity of the Mi-2u Nucleosome Remodeling and Deacetylase (NuRD) complex is controlled by the Ikaros family of lymphoid-lineage determining proteins. Ikaros, an integral component of the NuRD complex in lymphocytes, tethers this complex to active lymphoid differentiation genes, but keeps it in a functionally-poised state. Loss in Ikaros DNA binding activity causes a local increase in Mi-2u chromatin remodeling, histone deacetylation and suppression of lymphoid gene expression. The NuRD complex also redistributes to transcriptionally-poised non-Ikaros gene targets, involved in proliferation and metabolism, inducing their re-activation. Thus release of NuRD from Ikaros regulation blocks lymphocyte maturation and mediates progression to a leukemic state by engaging functionally-opposing epigenetic mechanisms and genetic networks. We used microarrays to detail the global programme of gene expression of mouse DP thymocyte after Ikaros inactivation with dominant negative of Ik at different stage. 8 samples (mouse DP thymocytes from wt, and different stage after Ikaros inactivation) are analyzed Mouse Microarray Expression platforms, Affymetrix Mouse 430 2.0. Examination of different histone modifications and binding sites for Ikaros, Mi2beta in wild type DP thymocytes, and Ikaros knockout thymocytes.

2011-11-13 | E-GEOD-32311 | biostudies-arrayexpress

MBD3 localization by ChIP-seq

Project description:Maintenance of chromatin structure is essential to eukaryotic life; dysregulation is known to be causal for aberrant development and disease. The Mi-2/nucleosome remodeling and histone deacetylase (NuRD) complex is a multiprotein machine proposed to regulate chromatin structure by nucleosome remodeling and histone deacetylation activities. We identified the localization of MBD3, a component of Mi-2/NuRD complex, in two breast cancer cell lines (MCF7 and MDA-MB-231) using ChIP-Seq. MBD3 showed cell-type specific localization with overlap across cell lines being less than 50%. MBD3 localized across gene bodies, peaking around the transcription start site (TSS). Contrary to existing models, MBD3 preferentially associated with CpG rich promoters marked by H3K4me3. These data suggest that MBD3, and by extension the Mi-2/NuRD complex, may have roles in fine tuning expression for active genes. These data represent an important first step in defining regulatory mechanisms by which Mi-2/NuRD complex controls chromatin structure and gene expression. Identification of MBD3 localization in human breast cancer cell lines

2013-10-31 | E-GEOD-44737 | biostudies-arrayexpress

Chromatin restriction by the nucleosome remodeler Mi-2β and functional interplay with lineage-specific transcription regulators controls B cell differentiation

Project description:Coordinated induction but also repression of genes is key to normal differentiation. Although the role of lineage-specific transcription regulators has been extensively studied, their functional integration with chromatin remodelers, one of the key enzymatic machineries that control chromatin accessibility, remains ill-defined. Here we investigate the role of Mi-2b, a SNF-2-like nucleosome remodeler and key component of the Nucleosome Remodeling Deacetylase (NuRD) complex in early B cells. Inactivation of Mi-2b arrested differentiation at the large pre-B cell stage and caused de-repression of cell adhesion and cell migration signaling factors by increasing chromatin access at poised enhancers and chromosome architectural elements. Mi-2b also supported IL-7R signaling, survival and proliferation by repressing negative effectors of this pathway. Importantly, over-expression of Bcl2, a mitochondrial pro-survival factor and target of IL-7R signaling, partly rescued the differentiation block caused by Mi-2b loss. Mi-2b stably associated with chromatin sites that harbor binding motifs for IKAROS and EBF1 and physically associated with these transcription factors both on and off chromatin. Notably, Mi-2b shared loss-of-function cellular and molecular phenotypes with IKAROS and EBF1 albeit in a distinct fashion. Thus the nucleosome remodeler Mi-2b promotes pre-B cell differentiation by providing repression capabilities to distinct lineage-specific transcription factor-based regulatory networks.

2019-05-15 | GSE130315 | GEO

DamID for MBD3 in human breast cancer cell lines [Promoter_Arrays]

Project description:Maintenance of chromatin structure is essential to eukaryotic life; dysregulation is known to be causal for aberrant development and disease. The Mi-2/nucleosome remodeling and histone deacetylase (NuRD) complex is a multiprotein machine proposed to regulate chromatin structure by nucleosome remodeling and histone deacetylation activities. We identified the localization of MBD3, a component of Mi-2/NuRD complex, in two breast cancer cell lines (MCF7 and MDA-MB-231) using ChIP-Seq. MBD3 showed cell-type specific localization with overlap across cell lines being less than 50%. MBD3 localized across gene bodies, peaking around the transcription start site (TSS). Contrary to existing models, MBD3 preferentially associated with CpG rich promoters marked by H3K4me3. These data suggest that MBD3, and by extension the Mi-2/NuRD complex, may have roles in fine tuning expression for active genes. These data represent an important first step in defining regulatory mechanisms by which Mi-2/NuRD complex controls chromatin structure and gene expression. DamID experiment was performed in human breast cancer cell lines (MCF-7 and MDA-MB-231) in duplicate. Samples were hybridized to Nimblegen 2.1M Deluxe promoter array. MBD3-Dam material was hybridized over Dam-only control.

2013-10-31 | E-GEOD-44773 | biostudies-arrayexpress

DamID for MBD3 in human breast cancer cell lines [Tiling Arrays]

Project description:Maintenance of chromatin structure is essential to eukaryotic life; dysregulation is known to be causal for aberrant development and disease. The Mi-2/nucleosome remodeling and histone deacetylase (NuRD) complex is a multiprotein machine proposed to regulate chromatin structure by nucleosome remodeling and histone deacetylation activities. We identified the localization of MBD3, a component of Mi-2/NuRD complex, in two breast cancer cell lines (MCF7 and MDA-MB-231) using ChIP-Seq. MBD3 showed cell-type specific localization with overlap across cell lines being less than 50%. MBD3 localized across gene bodies, peaking around the transcription start site (TSS). Contrary to existing models, MBD3 preferentially associated with CpG rich promoters marked by H3K4me3. These data suggest that MBD3, and by extension the Mi-2/NuRD complex, may have roles in fine tuning expression for active genes. These data represent an important first step in defining regulatory mechanisms by which Mi-2/NuRD complex controls chromatin structure and gene expression. DamID experiment was performed in human breast cancer cell lines (MCF-7 and MDA-MB-231) in triplicate. Samples were hybridized to NimbleGen Human Whole-Genome Tiling Arrays (0701_HG18_TILE_05_HX1 and 100718_HG18_TILE_05_HX1). MBD3-Dam material was hybridized over Dam-only control.

2013-10-31 | E-GEOD-44774 | biostudies-arrayexpress

DamID for MBD3 in human breast cancer cell lines [Tiling Arrays]

2013-10-31 | GSE44774 | GEO

DamID for MBD3 in human breast cancer cell lines [Promoter_Arrays]

2013-10-31 | GSE44773 | GEO

MBD3 localization by ChIP-seq

2013-10-31 | GSE44737 | GEO

Ikaros mediates gene silencing in T cells through Polycomb Repressive Complex 2 [ChIP-seq]

Project description:T cell development is accompanied by epigenetic changes that ensure the silencing of stem cell-related, and the activation of lymphocyte-specific programs. How transcription factors influence these changes remains unclear. We show that the Ikaros transcription factor interacts with the Polycomb Repressive Complex 2 (PRC2) in CD4-CD8- thymocytes, and allows its binding to >200 developmentally-regulated genes, many of which are expressed in hematopoietic stem cells. Loss of Ikaros in CD4-CD8- cells leads to diminished histone H3 Lys27 (H3K27) trimethylation and ectopic expression of these genes. Ikaros binding triggers PRC2 recruitment and H3K27 trimethylation. Furthermore, Ikaros interacts with PRC2 independently of the Nucleosome Remodeling and Deacetylation complex. Our results identify Ikaros as a fundamental regulator of PRC2 function in developing T cells. Genome-wide comparison of different histone modifications, Ikaros, Suz12 and NuRD binding in different stages of T cell development in WT and Ikaros mutant mice. Profiling of H3K27me3 in DN1, DN2, DN3, DN4 and DP thymocytes and hematopoietic stem and progenitor cells (LSK cells) of WT and Ikaros mutant mice. Profiling of H3K4me3 and H3ac in WT and Ikaros mutant DP thymocytes. Global analysis of Ikaros binding in WT DN3, DN4 and DP cells, Suz12 binding in WT and Ikaros mutant DN3 cells, and Mta2 and Mi2beta binding in WT DN3 cells. Genome-wide profiling of Ikaros binding and H3K27me3 upon Ikaros activation in Ikaros-deficient leukemic T cells.

2015-11-03 | E-GEOD-61148 | biostudies-arrayexpress

Regulation of Gene Expression Dynamics during Developmental Transitions by the Ikaros Transcription Factor

Project description:The DNA-binding protein, Ikaros, functions as a potent tumor suppressor and hematopoietic regulator. However, the mechanisms by which Ikaros functions in the nucleus remain largely undefined, due in part to its atypical DNA-binding properties and partnership with the poorly understood Mi-2/NuRD complex. In this study, we extended our analysis of thymocyte development and lymphomagenesis in a mouse strain containing a specific deletion of Ikaros zinc finger 4, which exhibits a select subset of abnormalities observed in Ikaros null mice. By examining thymopoiesis in vivo and in vitro, numerous abnormalities were observed. RNA-sequencing revealed that each developmental stage is characterized by mis-regulation of a limited number of genes, with a strong preference for genes modulated in a stage-specific manner. Strikingly, individual genes and pathways rarely exhibited Ikaros-dependence at all developmental stages. Instead, the most consistent feature of aberrantly expressed genes was a reduced magnitude of expression level change during a developmental transition. These results and others suggest that Ikaros may not be a dedicated and consistent activator or repressor of a defined set of genes. Instead, its primary function may be to support the dynamic range of gene expression changes during developmental transitions via atypical molecular mechanisms that remain undefined. RNA-Seq of T cells at varying developmental stages and T cells expressing activated Notch in WT and Ikzf1-dF4/dF4 mutant backgrounds

2015-08-21 | E-GEOD-67572 | biostudies-arrayexpress

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