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Reconstructing blood stem cell regulatory network models from single-cell molecular profiles.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Hamey, Fiona K 
Nestorowa, Sonia 
Kinston, Sarah J 
Kent, David G 
Wilson, Nicola K 

Abstract

Adult blood contains a mixture of mature cell types, each with specialized functions. Single hematopoietic stem cells (HSCs) have been functionally shown to generate all mature cell types for the lifetime of the organism. Differentiation of HSCs toward alternative lineages must be balanced at the population level by the fate decisions made by individual cells. Transcription factors play a key role in regulating these decisions and operate within organized regulatory programs that can be modeled as transcriptional regulatory networks. As dysregulation of single HSC fate decisions is linked to fatal malignancies such as leukemia, it is important to understand how these decisions are controlled on a cell-by-cell basis. Here we developed and applied a network inference method, exploiting the ability to infer dynamic information from single-cell snapshot expression data based on expression profiles of 48 genes in 2,167 blood stem and progenitor cells. This approach allowed us to infer transcriptional regulatory network models that recapitulated differentiation of HSCs into progenitor cell types, focusing on trajectories toward megakaryocyte-erythrocyte progenitors and lymphoid-primed multipotent progenitors. By comparing these two models, we identified and subsequently experimentally validated a difference in the regulation of nuclear factor, erythroid 2 (Nfe2) and core-binding factor, runt domain, alpha subunit 2, translocated to, 3 homolog (Cbfa2t3h) by the transcription factor Gata2. Our approach confirms known aspects of hematopoiesis, provides hypotheses about regulation of HSC differentiation, and is widely applicable to other hierarchical biological systems to uncover regulatory relationships.

Description

Keywords

Boolean network, gene regulatory networks, hematopoiesis, single cell, stem progenitor cells, Algorithms, Animals, Cell Differentiation, Gene Regulatory Networks, Hematopoiesis, Hematopoietic Stem Cells, Mice, Inbred C57BL, Transcription Factors

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

114

Publisher

Proceedings of the National Academy of Sciences
Sponsorship
Leukaemia & Lymphoma Research (12029)
Wellcome Trust (105031/D/14/Z)
National Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766)
Cancer Research UK (21762)
MRC (MR/K500975/1)
Leukemia & Lymphoma Society (7001-12)
MRC (MR/K50127X/1)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/M008975/1)
Bloodwise (15008)
Work in the author’s laboratory is supported by grants from Bloodwise, Cancer Research UK, Biotechnology and Biological Sciences Research Council, Leukemia Lymphoma Society, the National Institute for Health Research Cambridge Biomedical Research Centre and core support grants by the Wellcome Trust to the Cambridge Institute for Medical Research and Wellcome Trust-MRC Cambridge Stem Cell Institute. S.N. and F.K.H. are recipients of Medical Research Council PhD Studentships. D.G.K. is supported by a Bloodwise Bennett Fellowship (15008) and a European Hematology Association Non-Clinical Advanced Research Fellowship.