SUV39H1/2-mediated H3K9me3 restricts TE-induced immune response in Acute Myeloid Leukemia [ChIP-Seq]

Histone 3 Lysine 9 tri-methylation (H3K9me3) is a heterochromatin-associated histone mark deposited broadly across the genome and its regulation is required in normal hematopoiesis. Furthermore, H3K9me3 has been linked with 3D genome organization. However, in the context of acute myeloid leukemia (AML), the regulation of H3K9me3 and its function in 3D genome architecture remained understudied. In this study, through systematic Knockdowns and Knockouts, we identified SUV39H1 and by part its paralogue SUV39H2 as the major H3K9me3 depositors in AML. We demonstrated the role of SUV39H1/2 in establishing global H3K9me3 levels in AML cells and showed H3K9me3 depletion upon SUV39H1/2 Knockout preferentially occurred at sub-megabase level broad peaks and in GC poor regions. Loss of SUV39H1/2-mediated H3K9me3 poised AML cells towards monocyte/macrophage differentiation, induced TE re-activation and interferon response activation, and reduced AML cell growth and clonogenicity in vitro. Analysis of higher-order chromatin architecture reveals that while SUV39H1/2-mediated H3K9me3 is associated with a small fraction of larger chromatin structures, loss of SUV39H1/2 drives concomitant increase of H3K27me3 at B compartments. Taken together, our findings characterize the regulation of SUV39H1/2-mediated H3K9me3 and reveal its role in leukemogenesis and higher-order chromatin structure.