Fetal and adult hematopoietic stem cells (HSCs) have distinct proliferation rates, lineage biases, gene expression profiles, and gene dependencies. Although these differences are widely recognized, it is not clear how the transition from fetal to adult identity is coordinated. Here we show that murine HSCs and committed hematopoietic progenitor cells (HPCs) undergo a gradual, rather than precipitous, transition from fetal to adult transcriptional states. The transition begins prior to birth and is punctuated by a late prenatal spike in type I interferon signaling that promotes perinatal HPC expansion and sensitizes progenitors to the leukemogenic FLT3^ITD mutation. Most other changes in gene expression and enhancer activation are imprecisely timed and poorly coordinated. Thus, heterochronic enhancer elements, and their associated transcripts, are activated independently of one another rather than as part of a robust network. This simplifies the regulatory programs that guide neonatal HSC/HPC ontogeny, but it creates heterogeneity within these populations.

胎儿和成人造血干细胞 (HSC) 具有不同的增殖率、谱系偏差、基因表达谱和基因依赖性。尽管这些差异已得到广泛认可，但尚不清楚从胎儿身份到成人身份的过渡是如何协调的。在这里，我们展示了小鼠 HSC 和定型造血祖细胞 (HPC) 从胎儿到成人转录状态的过渡，而不是陡峭的过渡。这种转变在出生前就开始了，并被 I 型干扰素信号的晚期产前峰值打断，该信号促进围产期 HPC 扩增并使祖细胞对致白血病的 FLT3 ^ITD敏感突变。基因表达和增强子激活的大多数其他变化时间不精确且协调性差。因此，异时性增强子元件及其相关转录物彼此独立激活，而不是作为强大网络的一部分。这简化了指导新生儿 HSC/HPC 个体发育的监管程序，但它在这些人群中产生了异质性。