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Summary Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the mechanisms underlying its persistence and magnitude remain elusive. In this study, we show that BCG vaccination in healthy human volunteers induces a persistent transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell (HSPC) compartment in the bone marrow. We identify hepatic nuclear factor (HNF) family members 1a and b as crucial regulators of this transcriptional shift. These findings are corroborated by higher granulocyte numbers in BCG-vaccinated infants, HNF1 SNP variants that correlate with trained immunity, and elevated serum concentrations of the HNF1 target alpha-1 antitrypsin. Additionally, transcriptomic HSPC remodeling was epigenetically conveyed to peripheral CD14+ monocytes, displaying an activated transcriptional signature three months after BCG vaccination. Taken together, transcriptomic, epigenomic, and functional reprogramming of HSPCs and peripheral monocytes is a hallmark of BCG-induced trained immunity in humans., Graphical Abstract, Highlights • Human BCG vaccination induces a persistent innate immune training of CD14+ monocytes • BCG vaccination imprints a persistent transcriptomic myeloid bias on human HSPCs • Hepatic nuclear factors are regulators of BCG-induced trained immunity in HSPCs • BCG induces persistent epigenetic changes in peripheral CD14+ monocytes, Cirovic and de Bree et al. investigate the effects of BCG vaccination in humans and reveal the induction of a transcriptomic rewiring of human stem and progenitor cells toward the myeloid cell lineage, instructed by hepatic nuclear factors, resulting in epigenetic and functional changes within CD14+ peripheral monocytes.