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| Status |
Public on Nov 08, 2019 |
| Title |
Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Examination of binding profiles of GR, CTCF, H3K9ace, H3K27ace, H3K4me3 and H3K27me3 in combination with RNAseq, ATACseq and whole genome bisulfite sequencing data before and after Dex treatment in ALL xenograft cells.
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| Contributor(s) |
Jing D, Lock R, Huang Y, Beck D |
| Citation(s) |
30537513 |
| Submission date |
Jan 31, 2018 |
| Last update date |
Nov 29, 2019 |
| Contact name |
Yizhou Huang |
| E-mail(s) |
yizhou.huang1@unsw.edu.au
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| Organization name |
University of New South Wales
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| Street address |
High Street
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| City |
UNSW Sydney |
| State/province |
NSW |
| ZIP/Postal code |
2052 |
| Country |
Australia |
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| Platforms (1) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE109949 |
Lymphocyte-specific chromatin accessibility pre-determines glucocorticoid resistance in acute lymphoblastic leukemia |
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| Relations |
| BioProject |
PRJNA432402 |
| SRA |
SRP131901 |
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