Haematopoietic stem cells (HSCs) are multipotent, but individual HSCs can show restricted lineage output in vivo. Currently, the molecular mechanisms and physiological role of HSC fate restriction remain unknown. Here we show that lymphoid fate is epigenetically but not transcriptionally primed in HSCs. In multi-lineage HSCs that produce lymphocytes, lymphoid-specific upstream regulatory elements (LymUREs) but not promoters are preferentially accessible compared with platelet-biased HSCs that do not produce lymphoid cell types, providing transcriptionally silent lymphoid lineage priming. Runx3 is preferentially expressed in multi-lineage HSCs, and reinstating Runx3 expression increases LymURE accessibility and lymphoid-primed multipotent progenitor 4 (MPP4) output in old, platelet-biased HSCs. In contrast, platelet-biased HSCs show elevated levels of epigenetic platelet-lineage priming and give rise to MPP2 progenitors with molecular platelet bias. These MPP2 progenitors generate platelets with faster kinetics and through a more direct cellular pathway compared with MPP2s derived from multi-lineage HSCs. Epigenetic programming therefore predicts both fate restriction and differentiation kinetics in HSCs.

造血干细胞 (HSC) 具有多能性，但单个 HSC 在体内表现出有限的谱系输出。目前，HSC命运限制的分子机制和生理作用仍不清楚。在这里，我们表明，HSC 中淋巴命运是表观遗传而非转录引发的。与不产生淋巴细胞类型的血小板偏向性 HSC 相比，在产生淋巴细胞的多谱系 HSC 中，优先可接近淋巴特异性上游调节元件 (LymURE) 而不是启动子，从而提供转录沉默的淋巴谱系启动。Runx3优先在多谱系 HSC 中表达，恢复Runx3表达可增加旧的血小板偏向 HSC 中 LymURE 可及性和淋巴引发的多能祖细胞 4 (MPP4) 输出。相比之下，偏向血小板的 HSC 显示出表观遗传血小板谱系启动水平升高，并产生具有分子血小板偏向的 MPP2 祖细胞。与源自多谱系 HSC 的 MPP2 相比，这些 MPP2 祖细胞生成血小板的动力学更快，通过更直接的细胞途径。因此，表观遗传编程可以预测 HSC 的命运限制和分化动力学。