Research Resource: Transcriptional Response to Glucocorticoids in Childhood Acute Lymphoblastic Leukemia
Open Access
- 1 January 2012
- journal article
- Published by The Endocrine Society in Molecular Endocrinology
- Vol. 26 (1), 178-193
- https://doi.org/10.1210/me.2011-1213
Abstract
Glucocorticoids (GC) induce apoptosis in lymphoblasts and are thus essential in the treatment of acute lymphoblastic leukemia (ALL). Their effects result from gene regulations via the GC receptor (NR3C1/GR), but it is unknown how these changes evolve, what the primary GR targets are, and to what extent responses differ between ALL subtypes and nonlymphoid malignancies. We delineated the transcriptional response to GC on the exon level in a time-resolved manner in a precursor B- and a T childhood ALL model employing Exon microarrays and combined this with genome-wide NR3C1-binding site detection using chromatin immunoprecipitation-on-chip technology. This integrative approach showed that the response was strongly influenced by kinetics and extent of GR autoinduction in both models. Although remarkable differences between the ALL systems were apparent, we defined a set of common response genes enriched in apoptosis-related processes. Globally, GR binding was higher for GC-induced vs. -repressed genes, suggesting that GR mediates gene repression by interaction with distant enhancers or by cross talk with other transcription factors. Exon level analysis defined several new GC-regulated transcript variants of genes, including ATP4B, GPR98, TBCD, and ZBTB16. Our study provides unprecedented insight into the transcriptional response to GC in ALL cells, essential to understand this biologically and clinically important phenomenon. We found evidence of cell type-specific as well as common responses, possibly related to apoptosis induction, and detected induction of novel transcript variants by GC in the investigated systems. Finally, we implemented a bioinformatic framework that might be useful for high-density microarray analyses to identify alternative transcript variant expression.Keywords
This publication has 65 references indexed in Scilit:
- Chromatin accessibility pre-determines glucocorticoid receptor binding patternsNature Genetics, 2011
- Glucocorticoid use in acute lymphoblastic leukaemiaThe Lancet Oncology, 2010
- PLZF/ZBTB16, a glucocorticoid response gene in acute lymphoblastic leukemia, interferes with glucocorticoid-induced apoptosisThe Journal of Steroid Biochemistry and Molecular Biology, 2010
- Glucocorticoid receptor knock down reveals a similar apoptotic threshold but differing gene regulation patterns in T-cell and pre-B-cell acute lymphoblastic leukemiaMolecular and Cellular Endocrinology, 2010
- Molecular mechanisms regulating glucocorticoid sensitivity and resistanceMolecular and Cellular Endocrinology, 2009
- Alternative isoform regulation in human tissue transcriptomesNature, 2008
- Conservation analysis predicts in vivo occupancy of glucocorticoid receptor-binding sequences at glucocorticoid-induced genesProceedings of the National Academy of Sciences of the United States of America, 2008
- Genome-wide analysis of Polycomb targets in Drosophila melanogasterNature Genetics, 2006
- Identification of novel direct transcriptional targets of glucocorticoid receptorLeukemia, 2004
- Statistical significance for genomewide studiesProceedings of the National Academy of Sciences of the United States of America, 2003