SUMOylation inhibition potentiates the glucocorticoid receptor to program growth arrest of acute lymphoblastic leukemia cells (ATAC-seq)
Glucocorticoids (GCs) are a crucial component of effective treatment for acute lymphoblastic leukemia (ALL). GCs exert their functions through the glucocorticoid receptor (GR), a ligand-activated transcription factor (TF). Chromatin occupancy, chromatin-protein networks and gene programmes of GR are regulated by SUMOylation, which has therapeutic implications in other hematomalignancies. To unravel the GR-SUMO crosstalk in ALL, we induced a hypoSUMOylated state in NALM6 ALL cells with a SUMOylation inhibitor (ML-792). Genome-wide profiling of GR and SUMO binding and chromatin accessibility revealed that hypoSUMOylation augmented GR chromatin occupancy and altered chromatin openness upon dexamethasone (Dex) exposure. Association with transcriptome data indicated that on the novel binding sites GR predominantly suppressed target gene expression. Chromatin-proteomic analyses identified a substantial number of shared TFs and coregulators associated with chromatin-bound GR and SUMO. The chromatin-protein network of GR contained several TFs with corresponding binding motifs found on GR-adjacent chromatin sites, implying their simultaneous presence on chromatin. Cell cycle and proliferation analyses indicated that hypoSUMOylation potentiated Dex-induced cell cycle arrest and suppressed NALM6 cell proliferation, complementing the significant expression changes of cell cycle-related genes in our transcriptome data. Our work provides a valuable resource of GR chromatin partners and implies potential for targeting SUMOylation to increase sensitivity to GCs in ALL. Overall design: Examination of chromatin accessibility by ATAC-seq from NALM6 cells treated with or without Dex in the presence or absence of SUMOylation inhibitor ML792 (SUMOi). All sequencing was done with Illumina NextSeq 500.