Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Int J Mol Sci. 2022 May 5;23(9):5137. doi: 10.3390/ijms23095137.
Erythropoietin (EPO) signaling plays a vital role in erythropoiesis by regulating proliferation and lineage-specific differentiation of murine hematopoietic progenitor cells (HPCs). An important downstream response of EPO signaling is calcium (Ca) influx, which is regulated by transient receptor potential channel (TRPC) proteins, particularly TRPC2 and TRPC6. While EPO induces Ca influx through TRPC2, TRPC6 inhibits the function of TRPC2. Thus, interactions between TRPC2 and TRPC6 regulate the rate of Ca influx in EPO-induced erythropoiesis. In this study, we observed that the expression of TRPC6 in KIT-positive erythroid progenitor cells was regulated by DOT1L. DOT1L is a methyltransferase that plays an important role in many biological processes during embryonic development including early erythropoiesis. We previously reported that knockout () HPCs in the yolk sac failed to develop properly, which resulted in lethal anemia. In this study, we detected a marked downregulation of gene expression in progenitor cells in the yolk sac compared to the wild type (WT). The promoter and the proximal regions of the gene locus exhibited an enrichment of H3K79 methylation, which is mediated solely by DOT1L. However, the expression of , the positive regulator of Ca influx, remained unchanged, resulting in an increased TRPC2/TRPC6 ratio. As the loss of DOT1L decreased TRPC6, which inhibited Ca influx by TRPC2, HPCs in the yolk sac exhibited accelerated and sustained elevated levels of Ca influx. Such heightened Ca levels might have detrimental effects on the growth and proliferation of HPCs in response to EPO.
促红细胞生成素（EPO）信号通过调节小鼠造血祖细胞（HPC）的增殖和谱系特异性分化，在红细胞生成中发挥着至关重要的作用。EPO 信号的一个重要下游反应是钙（Ca）内流，其受瞬时受体电位通道（TRPC）蛋白调节，尤其是 TRPC2 和 TRPC6。EPO 通过 TRPC2 诱导 Ca 内流，而 TRPC6 抑制 TRPC2 的功能。因此，TRPC2 和 TRPC6 之间的相互作用调节 EPO 诱导的红细胞生成中 Ca 内流的速率。在这项研究中，我们观察到 KIT 阳性红系祖细胞中 TRPC6 的表达受 DOT1L 调节。DOT1L 是一种甲基转移酶，在胚胎发育过程中的许多生物学过程中发挥重要作用，包括早期红细胞生成。我们之前报道过，卵黄囊中 基因敲除（）HPC 不能正常发育，导致致命性贫血。在这项研究中，我们检测到与野生型（WT）相比，卵黄囊中 基因在祖细胞中的表达明显下调。基因座的启动子和近端区域显示出 H3K79 甲基化的富集，这仅由 DOT1L 介导。然而，Ca 内流的正调节剂 基因的表达保持不变，导致 TRPC2/TRPC6 比值增加。由于 DOT1L 的缺失减少了 TRPC6，TRPC6 通过 TRPC2 抑制 Ca 内流，因此卵黄囊中 基因敲除的 HPC 表现出加速和持续升高的 Ca 内流水平。这种升高的 Ca 水平可能对 HPC 对 EPO 的生长和增殖产生不利影响。
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