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

Cell Rep

Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Published: December 2019

AI Article Synopsis

  • Fetal hematopoietic stem cells (HSCs) transition into adult HSCs, showing significant changes in their functional properties during development.
  • Research involving deep sequencing of the genomes, epigenomes, and transcriptomes in mice reveals that while overall chromosomal organization remains conserved, adult HSCs exhibit greater compartmentalization and stronger boundary definitions.
  • The study highlights dynamic chromatin interactions within TADs, with specific transcription factors (TCF3 for fetal and NR4A1/GATA3 for adult HSCs) regulating stage-specific enhancer-promoter interactions, confirmed by loss-of-function tests for TCF3.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262670PMC
http://dx.doi.org/10.1016/j.celrep.2019.11.065DOI Listing

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