title: Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency.
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 andHmox1(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 ofBach1-/-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.
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.|Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.|Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hada
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.|Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Japan.
authors.forename: Ari
authors.initials: A
authors.lastname: Itoh-Nakadai
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.|Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Muto
authors.affiliation: Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Inoguchi
authors.affiliation: Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.|Laboratory of Genome and Epigenome Dynamics, Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Aichi, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ichiyanagi
authors.affiliation: Department of Research and Development, Cellspect Co. Ltd., Morioka, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Hojo
authors.affiliation: Division of Systems Bioscience for Drug Discovery, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Tomosugi
authors.affiliation: AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.|Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.|Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Harigae
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan igarashi@med.tohoku.ac.jp.|AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.|Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
mesh_terms: D000220:Adaptation, Biological; D018798:Anemia, Iron-Deficiency / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001773:Blood Cells / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D016000:Cluster Analysis; D019175:DNA Methylation; D004032:Diet; D004195:Disease Models, Animal; D004900:Erythroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005914:Globins / Q000235:genetics / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D063306:Mitophagy / Q000235:genetics; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D006418:Heme; D005914:Globins; D007501:Iron