Computational Modeling of a Transcriptional Switch Underlying B-Lymphocyte Lineage Commitment of Hematopoietic Multipotent Cells.

Abstract

Despite progresses in identifying the cellular mechanisms at the basis of the differentiation of hematopoietic stem/progenitor cells, little is known about the regulatory circuitry at the basis of lineage commitment of hematopoietic multipotent progenitors. To address this issue, we propose a computational approach to give further insights in the comprehension of this genetic mechanism. Differently from T lymphopoiesis, however, there is at present no mathematical model describing lineage restriction of multipotent progenitors to early B-cell precursors. Here, we provide a first model-constructed on the basis of current experimental evidence from literature and of publicly available microarray datasets-of the genetic regulatory network driving the cellular fate determination at the stage of lymphoid lineage commitment, with particular regard to the multipotent-B-cell progenitor transition. By applying multistability analysis methods, we are able to assess the capability of the model to capture the experimentally observed switch-like commitment behavior. These methods allow us to confirm the central role of zinc finger protein 521 (ZNF521) in this process, that we had previously reported, and to identify a novel putative functional interaction for ZNF521, which is essential to realize such characteristic behavior. Moreover, using the devised model, we are able to rigorously analyze the mechanisms underpinning irreversibility of the physiological commitment step and to devise a possible reprogramming strategy, based on the combined modification of the expression of ZNF521 and EBF1.