Chromatin state changes in HOXA9/MEIS1 leukemia cells [4C-Seq]

Aberrant expression of homeobox transcription factor HOXA9 is a central component of the leukemogenic program driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid progenitor cells and pro-B cells leads to significant rearrangement of the epigenetic landscape with prominent emergence of cancer specific de novo enhancers. HOXA9 acts as a pioneer factor at the de novo enhancers and is required for recruitment of transcription factor CEBP/a and the histone H3K4 methyltransferase MLL3/MLL4 complex. HOXA9 function at the de novo enhancer is distinct from its physiological role at distal enhancers during normal hematopoietic development. Genetic deletion of MLL3/4 specifically affects the active enhancer signatures at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis. Our study reveals a previously uncharacterized role of HOXA9 and the MLL3/4 complex in leukemogenesis and provide mechanistic insights in epigenetic deregulation during malignant transformation. Untransformed myeloid progenitors (MP), HOXA9/MEIS1-transformed myeloblasts (HMM cells) and HMM cells with HOXA9 inactivation were subjected to ChIP-seq, RNA-seq and 4C-seq for assessment of their chromatin states and transcriptomes. Untransformed pro-B cells and HOXA9/MEIS1-transformed proB lymphoblasts (HMB cells) were subjected to ChIP-seq for analysis of their chromatin states.