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

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          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.

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          Most cited references29

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          Beta-thalassemia.

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            Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network.

            The regulation and maintenance of systemic iron homeostasis is critical to human health. Iron overload and deficiency diseases belong to the most common nutrition-related pathologies across the globe. It is now well appreciated that the hormonal hepcidin/ferroportin system plays an important regulatory role for systemic iron metabolism. We review recent data that uncover the importance of the cellular iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network in systemic iron homeostasis. We also discuss how the IRE/IRP regulatory system communicates with the hepcidin/ferroportin system to connect the control networks for systemic and cellular iron balance.
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              Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy.

              GATA factors interact with simple DNA motifs (WGATAR) to regulate critical processes, including hematopoiesis, but very few WGATAR motifs are occupied in genomes. Given the rudimentary knowledge of mechanisms underlying this restriction and how GATA factors establish genetic networks, we used ChIP-seq to define GATA-1 and GATA-2 occupancy genome-wide in erythroid cells. Coupled with genetic complementation analysis and transcriptional profiling, these studies revealed a rich collection of targets containing a characteristic binding motif of greater complexity than WGATAR. GATA factors occupied loci encoding multiple components of the Scl/TAL1 complex, a master regulator of hematopoiesis and leukemogenic target. Mechanistic analyses provided evidence for crossregulatory and autoregulatory interactions among components of this complex, including GATA-2 induction of the hematopoietic corepressor ETO-2 and an ETO-2-negative autoregulatory loop. These results establish fundamental principles underlying GATA factor mechanisms in chromatin and illustrate a complex network of considerable importance for the control of hematopoiesis.
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                Author and article information

                Journal
                Haematologica
                Haematologica
                haematol
                Haematologica
                Haematologica
                Ferrata Storti Foundation
                0390-6078
                1592-8721
                March 2017
                2 December 2016
                : 102
                : 3
                : 454-465
                Affiliations
                [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
                Author notes

                MK and HK contributed equally to this work.

                Article
                1020454
                10.3324/haematol.2016.151043
                5394953
                27927768
                6f52640c-5d1b-4a78-b828-3b13cbf985ba
                Copyright©2017 Ferrata Storti Foundation

                Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.

                History
                : 15 June 2016
                : 01 December 2016
                Categories
                Articles
                Red Cell Biology & Its Disorders

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