BioProject

Blood production is maintained through adult life by haematopoietic stem cells which undergo a process of differentiation and increasing lineage restriction to produce all the terminal blood types. More...

Blood production is maintained through adult life by haematopoietic stem cells which undergo a process of differentiation and increasing lineage restriction to produce all the terminal blood types. The cell type transitions within this process are tightly controlled, and loss of control can lead to inappropriate proliferation and leukemic transformation. We and others have previously described seven transcriptional regulators (heptad; LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) which bind key haematopoietic genes in normal human CD34+ haematopoietic stem and progenitor cells (HSPCs). Heptad factors form a densely interconnected circuit by binding combinatorically at their own, and each other’s, regulatory elements. However, the precise role of the heptad throughout normal and leukemic haematopoiesis, including whether all seven factors act together in single cells, and whether heptad perturbation can influence cell fate decisions remain unclear. In this study we integrate bulk and single cell data in normal human HSPCs and leukemic cells and find that chromatin conformation at key heptad regulatory elements is predictive of cell identity in normal and leukemic progenitors. The interconnected heptad circuit identified in normal HSPCs persists in AML, but single cell transcriptomics suggest that specific heptad sub-circuits exist in individual cells, and we show that GATA2, TAL1 and ERG play key roles in regulating the stem to erythroid transition in both normal and leukemic contexts. Overall design: RNAseq of primary human CD34+ HSPCs lentivirally transduced with shRNAs targetting luciferse (control) or ERG. Less...