Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1188307 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31408019_1.fastq.gz | Fastqsanger.gz | |||
| SRR31408019_2.fastq.gz | Fastqsanger.gz | |||
| SRR31408020_1.fastq.gz | Fastqsanger.gz | |||
| SRR31408020_2.fastq.gz | Fastqsanger.gz | |||
| SRR31408021_1.fastq.gz | Fastqsanger.gz |
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Project description:LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study we systematically dissected the LMO2/LDB1 binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif R320LITR required for LMO2 binding. Most strikingly, co-expression of full length, wild type LDB1 increased LMO2 steady state abundance, whereas co-expression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Raw gene expression data on HSB-2 cells is presented here. RNAseq were performed on HSB cell lines to examine their expression patterns
2015-12-15 | E-GEOD-75839 | biostudies-arrayexpress
Project description:LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study we systematically dissected the LMO2/LDB1 binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif R320LITR required for LMO2 binding. Most strikingly, co-expression of full length, wild type LDB1 increased LMO2 steady state abundance, whereas co-expression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Raw gene expression data on HSB-2 cells is presented here.
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Project description:The transcriptional mediator LIM domain only 2 (LMO2) forms a large multi-protein complex together with TAL1/LYL1, HEB/E2A, LDB1 and GATA. This complex regulates transcription from the onset of haematopoietic development and during differentiation. Chromosomal re-arrangements involving LMO and other members of the complex are causative for T-cell lymphoblastic leukaemia (T-ALL). We have identified Plant Homeodomain (PHD)-like Finger 6 (PHF6) as a new LMO2 interacting factor. Somatic mutations in PHF6 have been found to occur in several types of leukaemia. We show that PHF6 interacts with LMO2 during the initial stages of the haematopoietic development, myeloid differentiation and in T-ALL. The LMO2/PHF6 complex binds the DNA and regulates linage-specific gene expression. Additionally, a loss or reduction of LMO2 and PHF6 leads to chromosomal instability. PHF6 and LMO2 are required for maintaining levels of γH2AX and 53BP1, where PHF6 is important for γH2AX accumulation and LMO2 has a role in recruiting 53BP1 to γH2AX foci.
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Project description:Many questions remain about how close association of genes and distant enhancers occurs and how this is linked to transcription activation. In erythroid cells, LDB1 is recruited to the β-globin locus via LMO2 and is required for looping of the β-globin locus control region (LCR) to the active β-globin promoter. We show that the LDB1 dimerization domain (DD) is necessary and, when fused to LMO2 is sufficient, to completely restore LCR-promoter looping and transcription in LDB1 depleted cells. The looping function of the DD is unique and irreplaceable by heterologous dimerization domains. Dissection of the DD revealed distinct functional properties of conserved subdomains. Notably, a conserved helical region (DD4/5) is dispensable for LDB1 dimerization and chromatin looping but essential for transcriptional activation. DD4/5 is required for the recruitment of the co-regulators FOG1 and NuRD complex. Lack of DD4/5 alters histone acetylation and RNA polymerase II recruitment and results in failure of the locus to migrate to the nuclear interior as normally occurs during erythroid maturation. These results uncouple enhancer-promoter looping from nuclear migration and transcription activation and reveal new roles for LDB1in these processes. RNA-seq in LDB1 knockdown, LDB1 delta4/5 construct, LDB1 full-length construct, and control in induced MEL cells; three replicates each.
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Project description:Substantial evidence supports the hypothesis that enhancers are critical regulators of cell type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of the LIM domain binding protein, LDB1/CLIM2/NLI, interacting with the enhancer binding protein, ASCL1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells. LDB1-mediated enhancer:promoter looping appears to be required for both activation and repression of these target target gene promoter genes. While LDB1-dependend activated genes are regulated at the level of transcriptional initiation, the LDB1-dependent repressed transcription units appear to be regulated primarily at the level of promoter pausing, with LDB1 regulating recruitment of MTA2, a component of the NuRD complex, on these negative enhancers, required for the repressive enhancer function. These results indicate that LDB1-dependent looping events can deliver repressive cargo to cognate promoters to mediate promoter pausing events in a pituitary cell type. ChIP assay followed by high throughput sequencing (ChIP-seq)
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Project description:Substantial evidence supports the hypothesis that enhancers are critical regulators of cell type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of the LIM domain binding protein, LDB1/CLIM2/NLI, interacting with the enhancer binding protein, ASCL1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells. LDB1-mediated enhancer:promoter looping appears to be required for both activation and repression of these target target gene promoter genes. While LDB1-dependend activated genes are regulated at the level of transcriptional initiation, the LDB1-dependent repressed transcription units appear to be regulated primarily at the level of promoter pausing, with LDB1 regulating recruitment of MTA2, a component of the NuRD complex, on these negative enhancers, required for the repressive enhancer function. These results indicate that LDB1-dependent looping events can deliver repressive cargo to cognate promoters to mediate promoter pausing events in a pituitary cell type. Global Run On (GRO) assay followed by high throughput sequencing (GRO-seq)
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Project description:Prolonged or enhanced expression of the proto-oncogene Lmo2 is associated with a severe form of T-cell Acute Lymphoblastic Leukemia (T-ALL), designated Early T-progenitor ALL (ETP-ALL), that is characterized by the aberrant self-renewal and subsequent oncogenic transformation of immature thymocytes. Recent data suggest that Lmo2 may exert these effects by functioning as component of a multi-subunit transcription complex that includes the ubiquitous adapter Ldb1 along with b-HLH and/or GATA family transcription factors. In this study, we investigated the importance of Ldb1 for Lmo2-induced T-ALL by conditional deletion of Ldb1 in thymocytes in a Lmo2 transgenic mouse model of T-ALL. Our results identify a critical requirement for Ldb1 in the induction of thymocyte self-renewal, thymocyte radio-resistance and transition to T-ALL in Lmo2 transgenic mice. Ldb1 was also required for acquisition of the pre-leukemic ETP gene expression signature in immature Lmo2 transgenic thymocytes. Together, these results support a model where Lmo2-induced T-ALL results from failure to down-regulate Ldb/Lmo2 nucleated transcription complexes that normally function to enforce self-renewal in bone marrow hematopoietic progenitors
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