Excessive fetal growth affects HSC quiescence maintenance through epigenetic programming of EGR1 transcriptional network

Abstract

SummaryFetal development is a critical period to shape stem cell identity and functions. Detrimental environments during this period are associated with epigenetics alteration of hematopoietic stem and progenitor cells (HSPC) with unknown functional impacts. We implemented a single-cell resolution integrative analysis combining epigenomics, transcriptomics, and functional data to elucidate the epigenetic influence associated with excessive fetal growth on HSPCs. We showed that hematopoietic stem cells (HSC) from large for gestational age neonates present a coordinated DNA hypermethylation and decrease expression for genes of the EGR1 transcriptional network including SOCS3, KLF2, and JUNB known to sustain stem cell quiescence and pluripotency. Furthermore, these changes were associated with a decreased ability for HSCs to stay undifferentiated and a decreased ability to expand in response to stimulation. Taken together, these results show that fetal overgrowth affects hematopoietic stem cells quiescence maintenance program through an epigenetic programming of the EGR1 related transcriptional network.