PU.1 Eviction at Lymphocyte-Specific Chromatin Domains Mediates Glucocorticoid Response in Acute Lymphoblastic Leukemia
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ABSTRACT:
PROVIDER: PRJNA988808 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25056069.fastq.gz | Fastqsanger.gz | |||
| SRR25056069_1.fastq.gz | Fastqsanger.gz | |||
| SRR25056069_2.fastq.gz | Fastqsanger.gz | |||
| SRR25056070.fastq.gz | Fastqsanger.gz | |||
| SRR25056070_1.fastq.gz | Fastqsanger.gz |
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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:Glucocorticoids are an essential part of many multi-agent treatment regimens for lymphoid malignancies where the emergence of glucocorticoid resistance is a significant barrier to a cure. We have previously identified that aberrant chromatin accessibility, at lymphocyte-specific glucocorticoid-response elements (GREs), is associated with drug resistance in acute lymphoblastic leukaemia (ALL). To gain a deeper understanding of regulatory mechanisms leading to these epigenetic alterations, we conducted a multi-omics study, to examine changes in chromatin conformation, following the in-vivo treatment of patient-derived xenografts (PDXs) with glucocorticoid i.e., dexamethasone (DEX). We found that glucocorticoid treatment led to distinct patterns of topological associated domains (TADs) in DEX sensitive and resistant ALLs. Pre-treatment, these TADs were primed by a development-related pioneer transcription factor PU.1, which also occupied GREs in glucocorticoid sensitive but not resistant ALLs. PU.1 binding was associated with lymphocyte-specific activation of GREs and GRE-interacting super-enhancers within the TADs. Furthermore, the PU.1-associated TADs modulated epigenetics and promoted expression of multiple genes, including BIM, ZBTB16, RASA1 and other genes mediating glucocorticoid-induced apoptosis in ALL. The inhibition of PU.1 enhanced sensitivity of ALL cells to glucocorticoid treatment. Overall, this study illustrated a link between the lineage-specific efficiency of glucocorticoids and the developmental epigenetic modulators and provides insights into the role of fundamental epigenetics in clinical practice.
2024-10-08 | GSE236085 | 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 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 ChIPseq component of the study.
2019-11-08 | GSE109946 | 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
Project description:Glucocorticoid stimulation induces regionalized gene responses within topologically associating domains
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Project description:Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia
| PRJNA432395 | ENA
Project description:Transcription-factor binding to cis-regulatory regions regulates the gene expression program of a cell, but occupancy is often a poor predictor of the gene response. Here, we show that glucocorticoid stimulation led to the reorganization of transcriptional coregulators MED1 and BRD4 within topologically associating domains (TADs), resulting in active or repressive gene environments. Indeed, we observed a bias toward the activation or repression of a TAD when their activities were defined by the number of regions gaining and losing MED1 and BRD4 following dexamethasone (Dex) stimulation. Variations in Dex-responsive genes at the RNA levels were consistent with the redistribution of MED1 and BRD4 at the associated cis-regulatory regions. Interestingly, Dex-responsive genes without the differential recruitment of MED1 and BRD4 or binding by the glucocorticoid receptor were found within TADs, which gained or lost MED1 and BRD4, suggesting a role of the surrounding environment in gene regulation. However, the amplitude of the response of Dex-regulated genes was higher when the differential recruitment of the glucocorticoid receptor and transcriptional coregulators was observed, reaffirming the role of transcription factor-driven gene regulation and attributing a lesser role to the TAD environment. These results support a model where a signal-induced transcription factor induces a regionalized effect throughout the TAD, redefining the notion of direct and indirect effects of transcription factors on target genes.
2023-07-19 | GSE226487 | GEO
Project description:A major class of chemotherapeutics targets topoisomerase II for DNA double-strand breaks and cancer cell elimination. We compare four members of this class?the anthracyclines doxorubicin, daunorubicin and aclarubicin that does not induce DNA breaks?and a different compound, etoposide. We define a novel activity for anthracyclines: histone eviction from open chromosomal areas. Since histone variant H2AX is also evicted, DNA damage response is attenuated when compared to etoposide. Histone eviction also affects the epigenetic code and deregulates the transcriptome in cancer cells and organs such as the heart. Histone eviction by anthracyclines can drive apoptosis of topoisomerase-negative acute myeloid leukemia blasts in patients. Doxo- and daunorubicin combine the activities of two anti-cancer drugs: etoposide for DNA damage and aclarubicin for histone eviction. We define a novel mechanism of action of anti-cancer drugs doxo- and daunorubicin on chromatin biology with profound consequences on DNA damage responses, epigenetics, transcription, side effects and anti-cancer activities. Comparison of histone occupancy of cells or tissues treated with topoisomerase II inhibitors to un-treated ones by FAIRE-seq.
2013-06-04 | E-GEOD-33632 | biostudies-arrayexpress