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Spatial genome re-organization between fetal and adult hematopoietic stem cells

C Chen, W Yu, J Tober, P Gao, B He, K Lee, T Trieu, GA Blobel, NA Speck, K Tan
doi: https://doi.org/10.1101/628214
C Chen
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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W Yu
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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J Tober
2Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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P Gao
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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B He
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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K Lee
3Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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T Trieu
4Department of Computer Science, University of Missouri-Columbia, Columbia, MO, 65211, USA
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GA Blobel
4Department of Computer Science, University of Missouri-Columbia, Columbia, MO, 65211, USA
5Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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NA Speck
2Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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K Tan
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
2Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
5Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
6Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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  • For correspondence: tank1@email.chop.edu
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Abstract

Fetal hematopoietic stem cells (HSCs) undergo a developmental switch to become adult HSCs. The functional properties of the HSCs change dramatically during this switch, including their cycling behavior, hematopoietic lineage outputs and proliferation rate. The relationship between three-dimensional (3D) genome organization, epigenomic state, and transcriptome is poorly understood during this critical developmental transition. Here we conducted a comprehensive survey of the 3D genome, epigenome and transcriptome of fetal and adult HSCs in mouse. We found that chromosomal compartments and topologically associating domains (TAD) 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, dynamics of intra-TAD chromatin interactions is much higher and more widespread, involving over a thousand gene promoters and distal enhancers. Such dynamic interactions target genes involved in cell cycle, metabolism, and hematopoiesis. These developmental-stage-specific enhancer-promoter interactions appear to be mediated by different sets of transcription factors in fetal and adult HSCs, such as TCF3 and MAFB in fetal HSCs, versus NR4A1 and GATA3 in adult HSCs. Loss-of-function studies of TCF3 confirms the role of TCF3 in mediating condition-specific enhancer-promoter interactions and gene regulation in fetal HSCs. In summary, our data suggest that the fetal-to-adult transition is accompanied by extensive changes in intra-TAD chromatin interactions that target genes underlying the phenotypic differences between fetal and adult HSCs.

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Posted May 05, 2019.
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Spatial genome re-organization between fetal and adult hematopoietic stem cells
C Chen, W Yu, J Tober, P Gao, B He, K Lee, T Trieu, GA Blobel, NA Speck, K Tan
bioRxiv 628214; doi: https://doi.org/10.1101/628214
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Spatial genome re-organization between fetal and adult hematopoietic stem cells
C Chen, W Yu, J Tober, P Gao, B He, K Lee, T Trieu, GA Blobel, NA Speck, K Tan
bioRxiv 628214; doi: https://doi.org/10.1101/628214

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