GSE115363
ESRRB regulates glucocorticoid gene expression in mice and patients with acute lymphoblastic leukemia
Synthetic glucocorticoids (GCs), such as dexamethasone and prednisone, remain key components of therapy for patients with lymphoid malignancies. For pediatric patients with acute lymphoblastic leukemia (ALL), response to GCs remains the most reliable prognostic indicator; failure to respond to GC correlates with poor event-free survival. To uncover GC resistance mechanisms, we performed a genome-wide, survival-based short hairpin RNA screen and identified the orphan nuclear receptor estrogen-related receptor-? (ESRRB) as a critical transcription factor that cooperates with the GC receptor (GR) to mediate the GC gene expression signature in mouse and human ALL cells. Esrrb knockdown interfered with the expression of genes that were induced and repressed by GR and resulted in GC resistance in vitro and in vivo. Dexamethasone treatment stimulated ESRRB binding to estrogen-related receptor elements (ERREs) in canonical GC-regulated genes, and H3K27Ac Hi-chromatin immunoprecipitation revealed increased interactions between GR- and ERRE-containing regulatory regions in dexamethasone-treated human T-ALL cells. Furthermore, ESRRB agonists enhanced GC target gene expression and synergized with dexamethasone to induce leukemic cell death, indicating that ESRRB agonists may overcome GC resistance in ALL, and potentially, in other lymphoid malignancies. Overall design: RNA-seq:  The effects of dexamethasone treatment on gene expression in mouse T-ALL cells. We examine how the gene expression response changes with repression of NR3C1 and ESRRB. HiChIP:  H3K27ac HiChIP analysis in mouse T-ALL cells to analyze active chromatin-chromatin interactions after treatment with DMSO or DEX Cells were crosslinked with formaldehyde for 10 min.  DNA was enriched by chromatin-immunoprecipitation (ChIP), tagmented with Tn5 and analyzed by BGISeq500.  HiChIP was performed using an antibody against H3K27ac Antibody  (ABCAM, ab4729).