Page 26 - 2019_10 resto del Mondo_web

H. Kato et al.
study. In addition, a barcoded progenitor cell transplan- tation analysis revealed that the majority of CMP can dif- ferentiate into only erythroid or myeloid cells after trans- plantation.15 Therefore, CMP are a highly heterogeneous population of progenitor cells, and the dominant popula- tions in CMP are already committed to erythroid or myeloid differentiation. However, it should be noted that these findings were obtained from a “snapshot” analysis, which may have overlooked the plasticity of differentiation potential or gene expression patterns in CMP. Indeed, the introduction of specific TF (such as GATA-1 and DDIT3) into myeloid lineage progenitors can switch the lineage output to the erythroid lineage, suggesting the existence of plasticity under the control of TF in erythroid-myeloid progenitors.53,54 This idea is not surprising when we consider the fact that TF often alter the epigenetic modifications for lineage commitment (e.g., via pioneer TF55) and that epigenetic changes per se are reversible.56,57 Therefore, the observed subpopula- tions of CMP may show plasticity under physiological conditions, which can be masked during transplantation. In this context, it is still too early to conclude that CMP are heterogeneous populations of already committed progenitors. Further investigations combining single-cell chasing with the comprehensive measurement of epigenomes and transcriptomes in unperturbed condi- tions will be needed.
In the view of the gene regulatory networks at the ery- throid-myeloid bifurcation, key TF, including the CCAAT-enhancer-binding protein (C/EBP) family,58,59 PU.160 and GATA-1,61 play essential roles in erythroid or myeloid differentiation, which might operate the ery- throid-myeloid bifurcation at the level of CMP or multi- potent progenitors. Given that GATA-1 and PU.1 show mutually exclusive expression patterns during erythroid and myeloid differentiation and repress each other and activate themselves, the gene regulatory network of GATA1 and SPI1 (encoding PU.1) may determine the bifurcation of myeloid and erythroid cells.48 In this model, stochastic alterations in the ratio of GATA1 to PU.1 activity might initiate the differentiation. However, a recent study found that GATA1 and SPI1 are not co- expressed in CMP.62 Upon erythroid differentiation, the expression of GATA1 commences with a substantial lag after the cessation of SPI1 expression. In contrast, upon myeloid differentiation, no progenitor cells showed a period with GATA1 expression.62 Thus, GATA-1 may not be the initiator of erythroid differentiation but just the executor of the erythroid development from progenitor cells whose erythroid commitment has already been defined by unknown factors. Recent single-cell proteom- ic analyses additionally revealed that the TF KLF1 and FLI1 play important roles in the bifurcation of erythroid and megakaryocytes.63
Since erythroid cells and myeloid cells are rigorously produced from progenitor cells every day, as described above, there should exist a mechanism to fine tune the differentiation trajectory shift of erythroid-myeloid com- mon progenitor cells depending on the demand, which can vary with environmental changes. For instance, infections and inflammation induce myeloid differentia- tion and reduce erythroid differentiation, which can lead to anemia of inflammation. It has long been accepted that the major cause of this form of anemia is a disorder of iron utility for erythroid maturation caused by the
induction of hepcidin, which inhibits iron uptake and recycling.8 However, since iron supplementation for the treatment of anemia of inflammation is still controver- sial8,64 and infections as well as inflammation can induce a shift in the differentiation trajectory at the level of ery- throid-myeloid progenitors,65 there may be other factors that modulate the differentiation trajectory of progeni- tors, depending on environmental changes.
We recently reported that BACH factors are required for the efficient commitment of HSPC to an erythroid fate.19 BACH factors inhibit the expression of Cebpb, the gene encoding the TF C/EBPβ, which plays an indispen- sable role in emergency myelopoiesis.59 Importantly, BACH factors and C/EBPβ exert opposite effects on their downstream target genes: BACH factors repress a set of myeloid-affiliated genes, whereas C/EBPβ activates these genes at the same genomic loci. Since both BACH factors and the C/EBP family can bind to AP-1 motifs, the balance between repression and activation via the AP-1 motif appears to be critical for determining myeloid fate21,66 (Figure 2). Since infectious stimuli repress the expression of BACH factors and induce C/EBPβ expres- sion,18,19 the gene regulatory network of these TF genes can fluctuate in response to environmental input between two states, which correspond to erythroid and myeloid fates.
The gene regulatory network for lymphoid lineage commitment
Lymphoid cells are also derived from common progen- itor cells that possess the ability to differentiate into lym- phoid or myeloid cells. LMPP are now considered such common progenitors.1,34,52 Similar to the single-cell tran- scriptomic observations in CMP, a single-cell analysis of LMPP also showed that LMPP are a heterogeneous pop- ulation.14 For instance, a single-cell in vitro differentiation assay showed that most LMPP were only able to differ- entiate into either myeloid or lymphoid cells.14 Therefore, most LMPP may be cells whose differentia-
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.
1922
haematologica | 2019; 104(10)