Summary Excessive fetal growth is associated with DNA methylation alterations in human hematopoietic stem and progenitor cells (HSPC), but their functional impact remains elusive. We implemented an integrative analysis combining single-cell epigenomics, single-cell transcriptomics, and in vitro analyses to functionally link DNA methylation changes to putative alterations of HSPC functions. We showed in hematopoietic stem cells (HSC) from large for gestational age neonates that both DNA hypermethylation and chromatin rearrangement target a specific network of transcription factors known to sustain stem cell quiescence. In parallel, we found a decrease expression of key genes regulating HSC differentiation including EGR1, KLF2, SOCS3 , and JUNB . Our functional analyses showed that this epigenetic programming was associated with a decreased ability for HSCs to stay quiescent. Taken together, our multimodal approach using single-cell (epi)genomics showed that human fetal overgrowth affects hematopoietic stem cells quiescence maintenance via epigenetic programming.

Early epigenetic influence on EGR1, KLF2 and KLF4 transcriptional network associates with alteration of HSCs quiescence