Reconstructing Gene Regulatory Networks That Control Hematopoietic Commitment
Hematopoietic stem cells (HSCs) reside at the apex of the hematopoietic hierarchy, possessing the ability to self-renew and differentiate toward all mature blood lineages. Along with more specialized progenitor cells, HSCs have an essential role in mainta
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Introduction Due to their high turnover, hematopoietic cells require constant replacement in order to sustain the blood system throughout adult life. Extensive research over the past 60 years has revealed that hematopoietic stem and progenitor cells (HSPCs) at different stages of commitment can be found in the mammalian bone marrow, with cells from specific populations specified toward one or more of the more than ten different lineages of mature blood cells. This led to the popular view of a hematopoietic hierarchy, where hematopoietic stem cells (HSCs) can differentiate into increasingly specialized progenitor cell populations (Fig. 1a). Due to the accessibility of material and the existence of cell surface marker-based sorting strategies, these hematopoietic populations can be readily isolated and studied and so are well-characterized in comparison to
Patrick Cahan (ed.), Computational Stem Cell Biology: Methods and Protocols, Methods in Molecular Biology, vol. 1975, https://doi.org/10.1007/978-1-4939-9224-9_11, © Springer Science+Business Media, LLC, part of Springer Nature 2019
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Fiona K. Hamey and Berthold Go¨ttgens
Fig. 1 Single-cell snapshot gene expression data can be used to reconstruct the transcriptional landscape of hematopoiesis. (a) Hematopoietic stem cells (HSCs) reside at the apex of the hematopoietic hierarchy. These cells can differentiate toward all of the different blood lineages. Ery, erythroid; Mk, megakaryocytic; My, myeloid; Ly, lymphoid. (b) By sampling single cells from the bone marrow and profiling their gene expression, it is possible to capture cells at different stages of differentiation and build up a picture of the underlying transcriptional landscape. (c) Cells can be computationally ordered based on similarities in their transcriptional profile. This ordering, often described as “pseudotime,” aims to recapitulate molecular changes during differentiation. (d) Pseudotime orderings can be used to investigate the sequence of expression changes during differentiation for different markers
stem and progenitor cells in many other adult systems. The hematopoietic system, therefore, presents attractive opportunities for studying stem cell differentiation. 1.1 Transcription Factors as Key Regulators of Cell Fate Decisions
The hematopoietic system must maintain an appropriate balance of all mature cell types, as dysregulation of hematopoietic cell fate decisions is linked to potentially fatal blood disorders such as acute myeloid leukemia. It is therefore vital to understand how blood stem cells regulate their decision to differentiate toward alternative fates. Across many biological systems, it is well established that expression of genes encoding transcription factors plays an important role in determining cell fate decisions [1]. In particular, transcriptional regulation plays a central role in determining cell fate decisions and executing lineage differentiation in the blood [2].
1.2 Discovering Gene Regulatory Networks
In their role of driving specific lineage choices, t
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