The TET-dependent DNA demethylation pathway is the driving force of hematopoiesis

A complex network of signaling cascades regulates the differentiation of hematopoietic stem and progenitor cells (HSPCs) into mature blood cells during hematopoiesis. We demonstrated that DNA demethylation driven by Ten-Eleven Translocation (TET) enzymes controls the activity of multiple of these signaling cascades. This occurs because dozens of genes, essential for the specification (e.g., Gata1, Tcf7, Bcl11b, Pou2af1) and maturation (e.g., TCR and BCR signaling) of erythroblasts, T cells, and B cells, are highly methylated in HSPCs and must be demethylated by TET enzymes to be activated in their respective blood lineages. Many genes required for the maturation, but not for the specification, of monocytes and granulocytes are highly methylated in HSPCs, a condition that does not impede the emergence of these cells but can significantly impair their function. Loss of TET activity leads to severe impairment of hematopoiesis and results in hematological malignancies.