Nucleosome dynamics and gene expression in glucocorticoid-treated acute lymphoblastic leukemia, RS4 11
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA291621 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2138390.fastq.gz | Fastqsanger.gz | |||
| SRR2138400.fastq.gz | Fastqsanger.gz | |||
| SRR2138391.fastq.gz | Fastqsanger.gz | |||
| SRR2138401.fastq.gz | Fastqsanger.gz | |||
| SRR2138392.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 21 |
Similar Datasets
Project description:Precise nucleosome positioning is an increasingly recognized feature of promoters and enhancers, reflecting complex contributions of DNA sequence, nucleosome positioning, histone modification and transcription factor binding to enhancer activity and regulation of gene expression. Changes in nucleosome position and occupancy, histone variants and modifications, and chromatin remodeling are also critical elements of dynamic transcriptional regulation, but poorly understood at enhancers. We investigated glucocorticoid receptor-associated (GR) nucleosome dynamics at enhancers in acute lymphoblastic leukemia. For the first time, we demonstrate functionally distinct modes of nucleosome remodeling upon chromatin binding by GR, which we term central, non-central, phased, and minimal. Central and non-central remodeling reflect nucleosome eviction by GR and cofactors, respectively. Phased remodeling involves nucleosome repositioning and is associated with rapidly activated enhancers and induction of gene expression. Minimal remodeling sites initially have low levels of enhancerassociated histone modification, but the majority of these regions gain H3K4me2 or H3K27Ac to become de novo enhancers. Minimal remodeling regions are associated with gene ontologies specific to decreased B cell number and mTOR inhibition and may make unique contributions to glucocorticoid-induced leukemia cell death. Our findings form a novel framework for understanding the dynamic interplay between transcription factor binding, nucleosome remodeling, enhancer function, and gene expression in the leukemia response to glucocorticoids.
2015-10-01 | GSE71616 | GEO
Project description:Genome-wide nucleosome dynamics in glucocorticoid-treated acute lymphoblastic leukemia cell line, RS4 11
| PRJNA291622 | ENA
Project description:LC-MS data and DIA-NN search files relating to: PU.1 Eviction at Lymphocyte-Specific Chromatin Domains Mediates Glucocorticoid Response in Acute Lymphoblastic Leukemia.
Abstract: The epigenetic landscape plays a critical role in the onset and evolution of various malignancies, but its therapeutic utility remains underutilized. Glucocorticoids are an essential part of many multi-agent treatment regimens for lymphoid malignancies. However, the emergence of glucocorticoid resistance is a significant barrier to cure, which is in part due to epigenetic alterations, including aberrant chromatin accessibility and hypermethylation at lymphocyte-specific glucocorticoid-response elements (GREs). To gain a deeper understanding of regulatory mechanisms leading to these epigenetic alterations, we conducted a multi-omics study, including chromosome conformation capture sequencing (HiC), to examine changes in the 3D genome structure following the in vivo treatment of acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) with glucocorticoid. We found that glucocorticoid treatment led to distinct patterns of topologically associated domains (TADs) in glucocorticoid sensitive compared to resistant PDXs. Furthermore, we show that these TADs were primed by the development-related pioneer transcription factor PU.1, which extensively interacts with the glucocorticoid receptor (GR) exclusively in glucocorticoid-sensitive ALL PDXs. An integrative analysis of rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) and ChIP-seq revealed that PU.1 binding was associated with lymphocyte-specific activation of GREs and GRE-interacting super-enhancers. The PU.1-associated TADs modulated epigenetic marks, and particularly the eviction of PU.1 promoted GR binding and the expression of signature genes, including BIM, ZBTB16 and RASA1, mediating glucocorticoid-induced apoptosis in ALL. These findings were phenocopied using a PU.1 inhibitor DB2313 to restore glucocorticoid sensitivity in ALL. Taken together, this study identified a new epigenetic pathway integrating PU.1 priming and PU.1-GR interaction which ultimately leads to PU.1 eviction in ALL. This pathway provides the first link between the activity of a lineage-specific transcription factor and epigenetic modulators mediating the response to glucocorticoids and thus offers a new avenue to translate fundamental epigenetic research into the clinic.
2024-10-03 | MSV000096019 | MassIVE
Project description:Precise nucleosome positioning is an increasingly recognized feature of promoters and enhancers, reflecting complex contributions of DNA sequence, nucleosome positioning, histone modification and transcription factor binding to enhancer activity and regulation of gene expression. Changes in nucleosome position and occupancy, histone variants and modifications, and chromatin remodeling are also critical elements of dynamic transcriptional regulation, but poorly understood at enhancers. We investigated glucocorticoid receptor-associated (GR) nucleosome dynamics at enhancers in acute lymphoblastic leukemia. For the first time, we demonstrate functionally distinct modes of nucleosome remodeling upon chromatin binding by GR, which we term central, non-central, phased, and minimal. Central and non-central remodeling reflect nucleosome eviction by GR and cofactors, respectively. Phased remodeling involves nucleosome repositioning and is associated with rapidly activated enhancers and induction of gene expression. Minimal remodeling sites initially have low levels of enhancerassociated histone modification, but the majority of these regions gain H3K4me2 or H3K27Ac to become de novo enhancers. Minimal remodeling regions are associated with gene ontologies specific to decreased B cell number and mTOR inhibition and may make unique contributions to glucocorticoid-induced leukemia cell death. Our findings form a novel framework for understanding the dynamic interplay between transcription factor binding, nucleosome remodeling, enhancer function, and gene expression in the leukemia response to glucocorticoids. We used microarrays to measure changes in gene expression following treatment of cells with dexamethasone for 0, 8, or 24 hours.
2015-10-01 | GSE71615 | GEO
Project description:Expression data from glucocorticoid-treated acute lymphoblastic leukemia cell line, RS4 11
| PRJNA291623 | ENA
Project description:Gene expression data of glucocorticoid resistant and sensitive acute lymphoblastic leukemia cell lines for the article: Expression, regulation and function of phosphofructo-kinase/fructose-biphosphatases (PFKFBs) in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia cells Glucocorticoids (GCs) cause apoptosis and cell cycle arrest in lymphoid cells and constitute a central component in the therapy of lymphoid malignancies, most notably childhood acute lymphoblastic leukemia (ALL). PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2), a kinase controlling glucose metabolism, was identified by us previously as GC response gene in expression profiling analyses performed in children with ALL during initial systemic GC mono-therapy. Since deregulation of glucose metabolism has been implicated in apoptosis induction, this gene and its relatives PFKFB1, 3, and 4 were further analyzed. Expression analyses in additional ALL children, non-leukemic individuals and leukemic cell lines confirmed frequent PFKFB2 induction by GC in most systems sensitive to GC-induced apoptosis, particularly in T-ALL cells. The 3 other family members, in contrast, were not or weakly expressed (PFKFB1 and 4) or not induced by GC (PFKFB3). Conditional PFKFB2 over-expression in the CCRF-CEM T-ALL in vitro model revealed that its 2 splice variants (15A and 15B) did not have any detectable effect on survival or cell cycle progression. Moreover, neither PFKFB2 splice variant significantly affected sensitivity to, or kinetics of, GC-induced apoptosis. Our data suggest that, at least in the model system investigated, PFKFB2 is not an essential upstream regulator of the anti-leukemic effects of GC. Generation of the GC sensitive and resistant clones is described in Parson et al. FASEB J 2005 (Pubmed id 15637111). In brief GC sensitive clones were generated by limiting dilution subcloning from the GC sensitive T-ALL cell line CCRF-CEM-C7H2. To generate GC resistant clones the CCRF-CEM-C7H2 cell line was clutured in the presence of 10E-7 M dexametasone. Gene expression profiles of glucocorticoid (GC) resistant and sensitive T-ALL cells during GC treatment and corresponding control samples (cells treated with carrier control). GC induced regulation of PFKFB2 was determined in the various cell lines based on the expression intensities of the corresponding probe sets in GC treated and control samples.
2011-02-01 | E-GEOD-22152 | biostudies-arrayexpress
Project description:Dasatinib Overcomes Glucocorticoid Resistance in B-cell Acute Lymphoblastic Leukemia
| PRJNA884735 | ENA
Project description:Semi-synthetic glucocorticoids are used to treat a broad range of medical conditions including inflammation, autoimmunity, and lymphoid malignancies. While a large component of these effects can be attributed to glucocorticoid-induced apoptosis of normal and malignant lymphocyte, the molecular basis for the lymphocyte-specific apoptosis remains unclear. Moreover, the mechanisms of glucocorticoid resistance in lymphoid malignancy are poorly defined, and remain a significant barrier to cure. To address these issues, we first performed a global analysis of chromatin accessibility in lymphoid and non-lymphoid cells to map lymphocyte-specific open chromatin domains (LSOs). We then integrated these domains with glucocorticoid receptor (GR) binding-induced RNA transcription and chromatin modulation in an in vivo patient-derived xenograft (PDX) model of acute lymphoblastic leukemia (ALL). This led to the identification of LSOs associated with glucocorticoid resistance in ALL. One such LSO was at the pro-apoptotic BIM gene locus, where a chromatin architectural protein CTCF binding was found only in lymphocytes but not in other cell types. The GR cooperated with CTCF to mediate interactions between the BIM promoter and the LSO to direct DNA looping, thus triggering BIM transcription. Importantly, this LSO was heavily DNA methylated in glucocorticoid resistant PDXs and non-lymphoid cells. This study demonstrates for the first time that lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in ALL and proposes a model for the lack of glucocorticoid sensitivity in non-lymphoid cell types. This submission represents the WGBS component of the study.
2019-11-08 | GSE109948 | GEO
Project description:Semi-synthetic glucocorticoids are used to treat a broad range of medical conditions including inflammation, autoimmunity, and lymphoid malignancies. While a large component of these effects can be attributed to glucocorticoid-induced apoptosis of normal and malignant lymphocyte, the molecular basis for the lymphocyte-specific apoptosis remains unclear. Moreover, the mechanisms of glucocorticoid resistance in lymphoid malignancy are poorly defined, and remain a significant barrier to cure. To address these issues, we first performed a global analysis of chromatin accessibility in lymphoid and non-lymphoid cells to map lymphocyte-specific open chromatin domains (LSOs). We then integrated these domains with glucocorticoid receptor (GR) binding-induced RNA transcription and chromatin modulation in an in vivo patient-derived xenograft (PDX) model of acute lymphoblastic leukemia (ALL). This led to the identification of LSOs associated with glucocorticoid resistance in ALL. One such LSO was at the pro-apoptotic BIM gene locus, where a chromatin architectural protein CTCF binding was found only in lymphocytes but not in other cell types. The GR cooperated with CTCF to mediate interactions between the BIM promoter and the LSO to direct DNA looping, thus triggering BIM transcription. Importantly, this LSO was heavily DNA methylated in glucocorticoid resistant PDXs and non-lymphoid cells. This study demonstrates for the first time that lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in ALL and proposes a model for the lack of glucocorticoid sensitivity in non-lymphoid cell types. This submission represents the RNAseq component of the study.
2019-11-08 | GSE109947 | GEO
Project description:Semi-synthetic glucocorticoids are used to treat a broad range of medical conditions including inflammation, autoimmunity, and lymphoid malignancies. While a large component of these effects can be attributed to glucocorticoid-induced apoptosis of normal and malignant lymphocyte, the molecular basis for the lymphocyte-specific apoptosis remains unclear. Moreover, the mechanisms of glucocorticoid resistance in lymphoid malignancy are poorly defined, and remain a significant barrier to cure. To address these issues, we first performed a global analysis of chromatin accessibility in lymphoid and non-lymphoid cells to map lymphocyte-specific open chromatin domains (LSOs). We then integrated these domains with glucocorticoid receptor (GR) binding-induced RNA transcription and chromatin modulation in an in vivo patient-derived xenograft (PDX) model of acute lymphoblastic leukemia (ALL). This led to the identification of LSOs associated with glucocorticoid resistance in ALL. One such LSO was at the pro-apoptotic BIM gene locus, where a chromatin architectural protein CTCF binding was found only in lymphocytes but not in other cell types. The GR cooperated with CTCF to mediate interactions between the BIM promoter and the LSO to direct DNA looping, thus triggering BIM transcription. Importantly, this LSO was heavily DNA methylated in glucocorticoid resistant PDXs and non-lymphoid cells. This study demonstrates for the first time that lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in ALL and proposes a model for the lack of glucocorticoid sensitivity in non-lymphoid cell types. This submission represents the ATACseq component of the study.
2019-11-08 | GSE109945 | GEO