3D chromatin topography of LSK cells with hyperactivated Notch1 and/or Tcf7 knock-out [HiC-seq]

NOTCH1 is a well-established lineage specifier for T cells and amongst the most frequently mutated genes throughout all subclasses of T cell acute lymphoblastic leukemia (T-ALL). How oncogenic NOTCH1 signaling launches a leukemia-prone chromatin landscape during T-ALL initiation is unknown. Here we demonstrate an essential role for the high-mobility-group transcription factor Tcf1 in orchestrating chromatin accessibility and topology allowing for aberrant Notch1 signaling to convey its oncogenic function. Although essential, Tcf1 is not sufficient to initiate leukemia. The formation of a leukemia-prone landscape at the distal Notch1-regulated Myc enhancer, which is fundamental to this disease, is Tcf1-dependent and occurs within the earliest progenitor stage even before cells adopt a T lymphocyte or leukemic fate. Moreover, we discovered an additional evolutionarily conserved Tcf1-regulated enhancer element, in the distal Myc-enhancer, which is important for the transition of pre-leukemic cells to full-blown disease. Chromatine conformation comparisons of sorted LSK derived from C57BL/6J; Sv/129 compound mice with Notch1 induced or Tcf1 knocked-down. Please note that the following files were generated per each condition and are linked to the corresponding replicate 1 sample records: Contact matrices hic files: 2 different resolutions (i.e. 2 per condition) TADs: bedpe files labeled like _5000_blocks.bedpe contain the TADs at resolution 5000Kb, one per contition Chromatin loops: bedpe files labeled _postprocessed_pixels_XXXX.bedpe where XXXX is the resolutions 2500Kb and there every 1000Kb from 5000 to 25000 (i.e. 22 per contition)