دانلود رایگان مقاله تنظیم بازوفیل و توسعه ماست سل توسط عوامل رونویسی

abstract

Basophils and mast cells play important roles in host defense against parasitic infections and allergic responses. Several progenitor populations, either shared or specific, for basophils and/or mast cells have been identified, thus elucidating the developmental pathways of these cells. Multiple transcription factors essential for their development and the relationships between them have been also revealed. For example, IRF8 induces GATA2 expression to promote the generation of both basophils and mast cells. The STAT5-GATA2 axis induces C/EBPa and MITF expression, facilitating the differentiation into basophils and mast cells, respectively. In addition, C/EBPa and MITF mutually suppress each other's expression. This review provides an overview of recent advances in our understanding of how transcription factors regulate the development of basophils and mast cells.

Discussion

As described above, the pathways and key transcription factors for the development of basophils and mast cells have been elucidated (Fig. 3). Specifically, GATA2 expression by IRF8 in GPs, and the induction of C/EBPa and MITF expression by the STAT5-GATA2 cascade in bipotential progenitors (pre-BMPs and possibly BMCPs) and downstream cells appear to be essential for promoting basophil and mast cell development. Because IRF8 is no longer expressed at the bipotential progenitor and downstream cell stages, it is conceivable that STAT5 takes over from IRF8 to induce GATA2 expression. Moreover, the mutually exclusive expression of C/EBPa and MITF underlies the basophil versus mast cell fate. In addition, IKAROS downregulates C/EBPa expression to suppress differentiation into basophils, presumably after the pre-BMP and BMCP stages. Nevertheless, target genes of these transcription factors are not yet known on a genome scale. Therefore, ChIP-seq analyses of transcription factors and various histone modifications will be key for future studies. In addition, though various progenitors have been identified, their exact relationships and whether they are homogenous populations are still obscure. To resolve these issues, transcriptome analyses using single-cell RNA-seq and detailed cell tracking experiments are required. Indeed, in a recent study, single cell RNA-seq analysis of early myeloid progenitors (lineage markers
Sca1
c-Kitþ cells) indicated that these cells might be already transcriptionally primed toward a single cell lineage such as basophils.61 Moreover, the analyses of several transcription factor-deficient mice would have to be re-conducted based on the current knowledge of the basophil and mast cell developmental pathways. Lastly, whether any changes in these developmental pathways occur with infections and allergies is still obscure. We expect that a deeper understanding of the differentiation of basophils and mast cells will contribute to the development of new therapies that control the production of basophils and mast cells.