LSD1-mediated repression of GFI1 super-enhancer plays an essential role in erythroleukemia

摘要: Super-enhancers (SEs) consist of enhancer clusters with abundant binding transcription factors (TFs) and cofactors. LSD1 is a histone modifier that eliminates SE activity. However, whether suppression by associated leukemogenesis remains unknown. In erythro-megakaryocyte lineage leukemia cells, activation the GFI1 (GFI1-SE) related to induction myeloid differentiation inhibitors NCD38 NCD25 their antileukemia effect. Although functional TF-motifs were concentrated in an evolutionally conserved area, barely induced additional TF recruitment. Instead, cofactors including LSD1, CoREST, HDAC1, HDAC2 evicted from GFI1-SE. Deletion GFI1-SE impaired erythroleukemia cells. Gene set enrichment analysis revealed deletion NCD38-induced programs granulocyte CEBPA network, but restored NCD38-suppressed erythroid development, GATA1 targets, acute (AML) FAB subtype M6 AML myelodysplastic syndrome-related chromosomal abnormalities. Ontologies genes whose expression changes canceled due showed neutropenia signatures. Collectively, our data suggest sustainable repression essential for sustenance