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  • Here we show that Jmjd a zebrafish JmjC domain containing

    2021-09-18

    Here, we show that Jmjd3, a zebrafish JmjC domain-containing protein, possesses H3K27 histone demethylase activity in vivo, and down-regulation of jmjd3 leads to significant reduction of primitive and definitive myelopoiesis. Importantly, we have demonstrated that jmjd3 directly upregulates spi1 expression to promote myeloid commitment in a histone demethylase-dependent manner. Our data, therefore, delineate the biology and the underline mechanism of jmjd3 function during normal myelopoiesis.
    Materials and methods
    Results
    Discussion Hematopoiesis is a complex process of producing all types of blood SB 204070 receptor including granulocytes and monocytes/macrophages. The differentiation and activation of myeloid cells require a timely regulation of gene expression, which depends on the interplay between transcription factors and epigenetic regulation, including histone modifications [54]. With this in mind, we screened systematically for both histone methyltransferases [54] and demethylases in zebrafish as epigenetic regulators of hematopoiesis during early development. Several genes with enriched expression in hematopoietic sites were identified, one of them is Jmjd3, an H3K27me3/2-specific demethylase that promotes gene transcription in many biological processes such as senescence and differentiation. In the hematopoietic system, Jmjd3 has been reported to be involved in M2 macrophage differentiation and terminal thymocyte development [29,30]. However, the roles of Jmjd3 in normal myelopoiesis are poorly understood. In this study, our results suggest that jmjd3 participates in the induction of myelopoiesis. Deficiency of Jmjd3 expression resulted in a decrease of myeloid development, at the same time, it resulted in an expansion of erythroid development as measured by the primitive erythroid progenitor marker gata1 at 20 hpf, the mature erythrocyte markers β-E3 at 22 hpf, and α-E1 globin at 22 hpf and 36 hpf. Similarly, previous work of a large-scale reverse genetic screen found that knockdown of jmjd3 promotes mature erythrocyte markers β-E3 expression at 17 hpf [55]. Consistently, Peripheral blood CD34+ progenitor cells in patients with lower-risk MDS (myelodysplastic syndromes) have increased expression of JMJD3 and an increased ability to form erythroid colonies upon inhibition of JMJD3 [56]. This suggests that Jmjd3 is intimately involved in erythroid lineage determination. Furthermore, Jmjd3 conditional knockout mice also exhibit a decrease of myeloid progenitors including granulocyte/monocyte progenitors (GMPs) in bone marrow (unpublished data) [57]. Specification of primitive hematopoietic progenitors into either myeloid or erythroid lineages is controlled by orchestrating the expression of a series of key transcription factors. It is well documented that spi1 and gata1 negatively regulate each other and the interplay between these two factors determines myeloid versus erythroid cell fate [43,44]. Also, tif1γ has been shown to regulate erythroid versus myeloid cell fates by controlling the expression levels of spi1 and gata1 [58]. Gfi1.1 is another myeloid transcriptional factor that governs the balance of primitive erythroid and myeloid lineage determination. Blocking gfi1.1 function by morpholino knockdown leads to a reduced expression of gata1 and increased expression of spi1 [59]. In addition to the transcriptional regulation, post-translational modifications are also important for myeloid-erythroid lineage choice. It has been reported that hyposumoylation of C/ebpα a leads to expansion of myeloid lineage at the expense of erythroid lineage, suggesting that sumoylation of C/ebpα is important for the differentiation control of erythroid-myeloid progenitors [60]. In this study, we demonstrated that jmjd3 bias the myeloid commitment at the expense of the erythroid commitment. Thus, cross-talk between transcription factors and epigenetic regulators may have synergistic effects in myeloid fate decisions.