| Systems biology is a discipline that attempts to understand the complexity of the organism at the system level,by constructing the model based on the integration of data or the analysis of the interactions among molecules.The endogenous molecular-cellular network theory was established based on the ideas of systems biology,which provides an approach to decipher the complexity of cellular behavior from molecular regulatory networks.In this paper,the endogenous network theory was applied to decode the hematopoietic lineage commitments.Understanding the regulatory mechanism of cell-fate decision and the formation and maintenance of hematopoietic homeostasis is of great significance to the study of blood diseases and regenerative medicine.Based on the observations from molecular cell biology,a step-wise and hierarchical classical hematopoietic lineage differentiation roadmap has been constructed,in which hematopoietic stem cells or multipotent progenitor cells differentiate into hematopoietic progenitor cells with restricted differentiation potential,and ultimately lead to various terminally differentiated cells.Although individual transcription factors acting on the regulation of hematopoietic lineage differentiation have been extensively studied,the mechanism of their cooperative regulation is difficult to be studied at the overall level.With the improvement of experimental techniques,the identification of heterogeneous progenitors and their potency challenged the classical differentiation roadmap.In addition,cell differentiation routes that are different from the classical differentiation roadmap were observed and modified the classical differentiation roadmap.In a word,there is no consensus on the global landscape of hematopoietic lineage differentiation yet.We demonstrated that the process of hematopoietic lineage differentiation can be reproduced in the landscape which “emerges” from the dynamics of the coarse-grained endogenous network.The network was based on the transcription factors that play critical roles at each cell-fate branchpoint and interactions among them.In addition,the emergent properties of nonlinear dynamical systems lead to the predictions of system properties that cannot be observed from an individual gene or regulatory relationship.The main results of this study are 1.The model predicted the self-activation of IKAROS and this regulation was validated in high-throughput data;2.The model predicted previously undercharacterized heterogeneous multipotent hematopoietic progenitors MPP1 and MPP2,which mediate different differentiation routes and the prediction was verified by single-cell transcriptome data;3.The model predicted that in the distinct developmental routes of erythrocyte/megakaryocyte lineage,different switch-like gene antagonisms played a pivotal role at the origin of the MPP differentiation.4.That the perturbations on the network resulted in state transitions indicated the impact of the ectopic gene expression in cellular phenotype conversions.In conclusion,our approach confirms known aspects of hematopoiesis and provides a predictive model to excavate the possible regulatory mechanism of the hematopoietic differentiation. |
