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Nat Immunol. 2018 Oct;19(10):1059-1070. doi: 10.1038/s41590-018-0202-3. Epub 2018 Sep 24.

Infection perturbs Bach2- and Bach1-dependent erythroid lineage 'choice' to cause anemia.

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
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
4
Department of Experimental Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
5
Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
6
Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.
7
Japan Society for the Promotion of Science, Tokyo, Japan.
8
Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, MD, USA.
9
Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan.
10
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
11
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
12
Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
13
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan. igarashi@med.tohoku.ac.jp.
14
Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan. igarashi@med.tohoku.ac.jp.

Abstract

Elucidation of how the differentiation of hematopoietic stem and progenitor cells (HSPCs) is reconfigured in response to the environment is critical for understanding the biology and disorder of hematopoiesis. Here we found that the transcription factors (TFs) Bach2 and Bach1 promoted erythropoiesis by regulating heme metabolism in committed erythroid cells to sustain erythroblast maturation and by reinforcing erythroid commitment at the erythro-myeloid bifurcation step. Bach TFs repressed expression of the gene encoding the transcription factor C/EBPβ, as well as that of its target genes encoding molecules important for myelopoiesis and inflammation; they achieved the latter by binding to their regulatory regions also bound by C/EBPβ. Lipopolysaccharide diminished the expression of Bach TFs in progenitor cells and promoted myeloid differentiation. Overexpression of Bach2 in HSPCs promoted erythroid development and inhibited myelopoiesis. Knockdown of BACH1 or BACH2 in human CD34+ HSPCs impaired erythroid differentiation in vitro. Thus, Bach TFs accelerate erythroid commitment by suppressing the myeloid program at steady state. Anemia of inflammation and myelodysplastic syndrome might involve reduced activity of Bach TFs.

PMID:
30250186
DOI:
10.1038/s41590-018-0202-3

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