Innate immune memory is a burgeoning field in immunology, yet there still remain many unanswered questions regarding its inherent duration in mitotic and post-mitotic cells, and its applicability in clinical settings. Clinically, the BCG vaccine is hypothesized to induce long-lasting innate immune memory in humans indirectly by reprogramming hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Although this model is supported by mouse studies, very little is known about whether reprogramming of HSPCs in response to BCG occurs in humans, and whether this has implications for the function of mature innate immune cells entering the peripheral circulation. In this work we first used single cell sequencing to probe the gene expression and chromatin accessibility landscape of human bone marrow samples before and 90 days after BCG vaccination and integrated these data with secondary response data collected on donor paired PBMCs. We find that the most uncommitted stem cells exhibit persistent signatures of myeloid bias and upregulation of immune genes. On the epigenetic level, downstream progenitors contained thousands of sites of differential accessibility at sites which enriched for the motifs of KLF/SP and EGR transcription factors which were predominantly active within upstream HSCs, suggesting that long-lasting TF activity and differential gene expression at the level of HSCs may impact the chromatin accessibility landscape of downstream progenitors. Myeloid bias, HSC activation signatures, and progenitor chromatin accessibility levels were all found to correlate significantly with Il1β secretion of donor paired PBMCs in response to a C. albicans challenge, indicating that BCG vaccination re-wires transcription factor activity, gene expression, chromatin accessibility, and lineage bias in human bone marrow in a way that is linked to responses of PBMCs to secondary immune challenge with non-mycobacterial pathogens.In addition, we utilized an in vitro macrophage model to study basic mechanisms by which innate immune memory can be retained within dividing cell populations. The encoding of innate immune memory has often been linked to histone post-translational modifications (PTMs). Since there is no known mechanism whereby stimulus-induced histone PTMs can be directly copied from parent to daughter strand during DNA replication, it is expected that these signatures be rapidly lost in dividing cells. Yet, in vivo studies have demonstrated that a state of trained immunity can persist for months, which paradoxically suggests that histone PTMs may persist. Using time course RNA-seq, ChIP-seq, and functional assays, we find that dividing macrophages harbor H3K4me1 signatures at hundreds of sites for at least 14 cell divisions after stimulus washout, however these marks are dynamic, timepoint specific, and tightly coupled to the continued activity of transcription factor (TF) circuits. Our work emphasizes the central role of continued TF activation in driving the continued detection of H3K4me1 signatures across cell divisions and suggests that innate immune memory in dividing cells may be a phenomenon that is mechanistically separate from that observed in non-dividing cells.