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Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109949 | GEO | 2019/11/08

REPOSITORIES: GEO

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Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [WGBS]

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

Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [ATAC-seq]

2019-11-08 | GSE109945 | GEO

Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [RNA-seq]

2019-11-08 | GSE109947 | GEO

Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [ChIP-seq]

2019-11-08 | GSE109946 | GEO

Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia

Project description:Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia

| PRJNA432395 | ENA

Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [WGBS]

Project description:Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [WGBS]

| PRJNA432400 | ENA

Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [ChIP-seq]

Project description:Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [ChIP-seq]

| PRJNA432401 | ENA

Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [RNA-seq]

Project description:Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [RNA-seq]

| PRJNA432402 | ENA

Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [ATAC-seq]

Project description:Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [ATAC-seq]

| PRJNA432405 | ENA

Chromatin accessibility pre-determines glucocorticoid receptor binding patterns.

Project description:Development, differentiation and response to environmental stimuli are characterized by sequential changes in cellular state initiated by the de novo binding of regulated transcriptional factors to their cognate genomic sites. The mechanism whereby a given regulatory factor selects a limited number of in vivo targets from a myriad of potential genomic binding sites is undetermined. Here we show that up to 95% of de novo genomic binding by the glucocorticoid receptor, a paradigmatic ligand-activated transcription factor, is targeted to preexisting foci of accessible chromatin. Factor binding invariably potentiates chromatin accessibility. Cell-selective glucocorticoid receptor occupancy patterns appear to be comprehensively predetermined by cell-specific differences in baseline chromatin accessibility patterns, with secondary contributions from local sequence features. The results define a framework for understanding regulatory factor-genome interactions and provide a molecular basis for the tissue selectivity of steroid pharmaceuticals and other agents that intersect the living genome.

| S-EPMC6386452 | biostudies-literature

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