Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency.
Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency.
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DOI：
10.3324/haematol.2016.151043
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发表时间：
2017-03
期刊：
影响因子：
10.1
通讯作者：
Igarashi K
中科院分区：
文献类型：
--
作者：
Kobayashi M;Kato H;Hada H;Itoh-Nakadai A;Fujiwara T;Muto A;Inoguchi Y;Ichiyanagi K;Hojo W;Tomosugi N;Sasaki H;Harigae H;Igarashi K
铁作为血红素和血红蛋白的成分，在红细胞的氧转运中起着核心作用。铁和血红素在成红细胞成熟过程中的调节作用也很重要。转录因子Bach 1可能参与它们的调节作用，因为它被血红素的直接结合失活。为了解决Bach 1是否参与成红细胞对铁状态的反应，建立了诱导小鼠严重缺铁的低铁条件。缺铁条件下，成红细胞成熟过程中广泛的基因表达改变和线粒体自噬紊乱。与野生型小鼠相比，Bach 1 −/−小鼠在小鼠发育阶段表现出更严重的缺铁性贫血，并且一旦补充铁，恢复迟缓。在Bach 1的情况下，珠蛋白基因和Hmox 1（编码血红素加氧酶-1）的表达在缺铁的成红细胞中被去抑制，这表明Bach 1抑制这些基因在缺铁的成红细胞中平衡血红素和珠蛋白的水平。此外，在缺铁的Bach 1 −/−小鼠的成红细胞中观察到全基因组DNA甲基化的增加。这些发现揭示了铁作为成红细胞成熟中基因表达的调节剂的主要作用，并表明铁-血红素-Bach 1轴对于成红细胞适当适应铁缺乏以避免非血红素珠蛋白的毒性聚集是重要的。
Iron plays the central role in oxygen transport by erythrocytes as a constituent of heme and hemoglobin. The importance of iron and heme is also to be found in their regulatory roles during erythroblast maturation. The transcription factor Bach1 may be involved in their regulatory roles since it is deactivated by direct binding of heme. To address whether Bach1 is involved in the responses of erythroblasts to iron status, low iron conditions that induced severe iron deficiency in mice were established. Under iron deficiency, extensive gene expression changes and mitophagy disorder were induced during maturation of erythroblasts. Bach1−/− mice showed more severe iron deficiency anemia in the developmental phase of mice and a retarded recovery once iron was replenished when compared with wild-type mice. In the absence of Bach1, the expression of globin genes and Hmox1 (encoding heme oxygenase-1) was de-repressed in erythroblasts under iron deficiency, suggesting that Bach1 represses these genes in erythroblasts under iron deficiency to balance the levels of heme and globin. Moreover, an increase in genome-wide DNA methylation was observed in erythroblasts of Bach1−/− mice under iron deficiency. These findings reveal the principle role of iron as a regulator of gene expression in erythroblast maturation and suggest that the iron-heme-Bach1 axis is important for a proper adaptation of erythroblast to iron deficiency to avoid toxic aggregates of non-heme globin.