Dynamics of epigenome and 3D genome in hematopoietic stem cell development

Epigenetics often refers to the mechanisms altering gene expression without any changes of DNA sequence. Epigenetic mechanisms regulate cell type specific gene expression, cellular identity, development, and many disease progresses. Hematopoietic stem cells (HSCs) are self-renewing, somatic stem cells that give rise to all mature blood cell types. HSCs are derived from a subset of endothelial cells during early embryonic development. To date, a key gap in our knowledge is how epigenetic mechanisms control HSC emergence and maturation.

To fill this gap, we first mapped four histone modifications for the five key developmental stages of HSC emergence in mouse embryo. Histone modifications are key epigenetic features involved in transcriptional regulation. Using the combination of histone modification data, we identified 12000~17000 transcriptional enhancers across five developmental stages. To study the function of those enhancers, we utilized a computational too called IM-PET to link enhancers to the target genes. Using enhancer-promoter pairs, we constructed transcriptional regulation networks for each cellular transition during development and identified multiple known and novel key transcription factors.

Second, we compared 3-dimensional genome, another key feature to regulate gene expression, between fetal and adult HSCs. We found that higher-order genome structures maintain stable between fetal and adult HSCs. However, chromatin interactions within TADs exhibit substantial differences. We found that promoters within 23% (242/1039) of TADs undergo interaction changes. Systematic analysis for intra-TAD interactions reveals that KLF1 mediates condition-specific enhancer looping and regulation of genes involved in cell cycle.