Regulation of haematopoietic multipotency by EZH1

All haematopoietic lineages circulating in the blood of adult mammals derive from multipotent haematopoietic stem cells (HSCs)(1). Haematopoiesis in the mammalian embryo stands in stark contrast, with lineage-restricted progenitors arising first, independently of HSCs, and HSCs emerging only later in gestation(2,3). As best defined in the mouse, “primitive” progenitors first appear in the yolk sac (YS) at 7.5 days post-coitum (dpc)(2,3). Subsequently, erythroid-myeloid progenitors (EMPs) that express fetal hemoglobin(4), as well as fetal lymphoid progenitors(5) develop in the YS and the embryo proper, but these cells lack HSC potential. Ultimately, “definitive” HSCs with long-term, multilineage potential and the capacity to engraft irradiated adults emerge at 10.5 dpc from arterial endothelium in the aorta-gonad-mesonephros (AGM) and other haemogenic vasculature(3). The molecular mechanisms for reverse progression of haematopoietic ontogeny remain unexplained. We hypothesized that the definitive haematopoietic program might be actively repressed in early embryogenesis via epigenetic silencing(6), and that alleviating this repression would elicit multipotency in otherwise restricted haematopoietic progenitors. Here, we demonstrate that reduced expression of the Polycomb group protein EZH1 uncovers multi-lymphoid output from human pluripotent stem cells (PSCs) and precocious emergence of functional definitive HSCs at sites of primitive and/or EMP-biased haematopoiesis in vivo, identifying EZH1 as a repressor of haematopoietic multipotency in the early mammalian embryo.