Spatial Genome Re-organization between Fetal and Adult Hematopoietic Stem Cells

Abstract

Summary: Fetal hematopoietic stem cells (HSCs) undergo a developmental switch to become adult HSCs with distinct functional properties. To better understand the molecular mechanisms underlying the developmental switch, we have conducted deep sequencing of the 3D genome, epigenome, and transcriptome of fetal and adult HSCs in mouse. We find that chromosomal compartments and topologically associating domains (TADs) are largely conserved between fetal and adult HSCs. However, there is a global trend of increased compartmentalization and TAD boundary strength in adult HSCs. In contrast, intra-TAD chromatin interactions are much more dynamic and widespread, involving over a thousand gene promoters and distal enhancers. These developmental-stage-specific enhancer-promoter interactions are mediated by different sets of transcription factors, such as TCF3 and MAFB in fetal HSCs, versus NR4A1 and GATA3 in adult HSCs. Loss-of-function studies of TCF3 confirm the role of TCF3 in mediating condition-specific enhancer-promoter interactions and gene regulation in fetal HSCs. : A developmental transition occurs between fetal and adult hematopoietic stem cells. How the 3D genome folding contributes to this transition is poorly understood. Chen et al. show global genome organization is largely conserved, but a large fraction of enhancer-promoter interactions is re-organized and regulate genes contributing to the phenotypic differences. Keywords: 3D genome, hematopoiesis, enhancer-promoter interaction, epigenomics, transcriptome