To be red or white: lineage commitment and maintenance of the hematopoietic system by the "inner myeloid"

Abstract

Differentiation of hematopoietic stem and progenitor cells is tightly regulated depending on environmental changes in order to maintain homeostasis. Transcription factors direct the development of hematopoietic cells, such as GATA-1 for erythropoiesis and PU.1 for myelopoiesis. However, recent findings obtained from single-cell analyses raise the question of whether these transcription factors are "initiators" or just "executors" of differentiation, leaving the initiation of hematopoietic stem and progenitor cell differentiation (i.e. lineage commitment) unclear. While a stochastic process is likely involved in commitment, it cannot fully explain the homeostasis of hematopoiesis nor "on-demand" hematopoiesis in response to environmental changes. Transcription factors BACH1 and BACH2 may regulate both commitment and on-demand hematopoiesis because they control erythroid-myeloid and lymphoid-myeloid differentiation by repressing the myeloid program, and their activities are repressed in response to infectious and inflammatory conditions. We summarize possible mechanisms of lineage commitment of hematopoietic stem and progenitor cells suggested by recent findings and discuss the erythroid and lymphoid commitment of hematopoietic stem and progenitor cells, focusing on the gene regulatory network composed of genes encoding key transcription factors. Surprising similarity exists between commitment to erythroid and lymphoid lineages, including repression of the myeloid program by BACH factors. The suggested gene regulatory network of BACH factors sheds light on the myeloid-based model of hematopoiesis. This model will help to understand the tuning of hematopoiesis in higher eukaryotes in the steady-state condition as well as in emergency conditions, the evolutional history of the system, aging and hematopoietic disorders.

Figure 1.

Stochastic model of lineage commitment. Transcription factors (TF) A and TF B play important roles in determining cell differentiation. If these two TF activate themselves and work in a mutually exclusive manner, slight stochastic fluctuations that alter the ratio of TF A to B can affect cell fate.

Figure 2.

Control of myeloid gene expression by BACH and C/EBP transcription factors in a state of infection. The BACH and C/EBP transcription factors (TF) repress and activate, respectively, myeloid gene expression by binding the same genomic loci. Infection/inflammation-induced alteration of these TF can affect myeloid gene expression, depending on the environment.

Figure 3.

Gene regulatory networks controlling lymphoid cell differentiation. Several factors have been identified as important regulators of lymphoid cell differentiation commitment. Each factor works as an activator and/or repressor of other factors forming complex gene regulatory networks, suggesting the existence of a precise mechanism underlying lymphoid cell differentiation. However, how the activities of these factors are controlled at the initial point of lineage commitment remains unclear.

Figure 4.

Gene regulatory networks of BACH and C/EBP transcription factors for myeloid and non-myeloid gene expression. The transcription factor (TF) BACH represses C/EBP and myeloid genes and induces lymphoid/erythroid genes. In contrast, the TF C/EBP represses BACH and lymphoid/erythroid genes and induces myeloid genes. Therefore, both stochastic fluctuation and environment-derived changes in the expression of BACH and C/EBP can induce differentiation commitment in progenitor cells.

Figure 5.

The fortifying role of BACH for the next emergency. BACH factors support erythropoiesis and repress myelopoiesis in steady-state conditions. BACH2 in particular supports the development of memory B cells, non-IgM plasma cells, regulatory T cells and memory T cells in the steady state while repressing the development of IgM plasma cells and effector T cells. Since BACH factors support the development of the cells needed for the suppression of a previous emergency reaction and the preparation for the next emergency, BACH factors can be considered “fortifying factors”.