Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (ChIA-PET)

Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML/RARα, a major etiological agent in APL. Although PML/RARα is critical, the molecular mechanisms remains largely unknown. Here, using an inducible system, we comprehensively analyzed the 3D genome organization in myloid cells and its reorganizationn after PML/RARα induction, and performed additional analysis in patient-derived APL cells with native PML/RARα. We discovered that PML/RARα mediate extensive chromatin interactions genome-wide. Globally, it redefine the chromatin topology of the in myloid genome toward a more condensed configuration in APL cells; locally, it intrude RNAPII-associated interaction dmains, interrupt myeloid-specific transcription factors binding at enhancers and super-enahncers, and lead to transcriptional repression of genes critical for myeloid differentiation and maturation. Together, our results provide novel insights of a topological framework for PML/RARα’s roles in transforming myeloid into leukemia, likely a general mechanism for oncogenic fusion proteins in cancers. Three factors (PML/RARA fusion protein, CTCF and RNAPII)  associated chromatin interaction maps are generated and used for exploring 3D genome architecture changes with two APL cell lines (U937-PR9 and NB4) during the APL leukogenesis. Paired-end sequencing (2 ×150bp) was used for ChIA-PET libraries with Illumina Hiseq 2500 or Illumina Nextseq 500.