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Haematologica. 2017 Mar;102(3):454-465. doi: 10.3324/haematol.2016.151043. Epub 2016 Dec 7.

Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency.

Author information

1
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
2
Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
3
AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.
4
Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Japan.
5
Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.
6
Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
7
Laboratory of Genome and Epigenome Dynamics, Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Aichi, Japan.
8
Department of Research and Development, Cellspect Co. Ltd., Morioka, Japan.
9
Division of Systems Bioscience for Drug Discovery, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan.
10
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan igarashi@med.tohoku.ac.jp.

Abstract

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.

PMID:
27927768
PMCID:
PMC5394953
DOI:
10.3324/haematol.2016.151043
[Indexed for MEDLINE]
Free PMC Article

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