Department of Biochemistry, Tohoku University Graduate School of Medicine
Regulation of ferroptosis by BACH1
Ferroptosis is controlled by the coordinated transcriptional regulation of glutathione and labile iron metabolism by the transcription factor BACH1. 20200222
Ferroptosis is a new type of cell death dependent on iron. Ferroptosis was originally discovered in Ras-driven cancer cells and has been implicated in cancer and degenerative diseases. Dr. Nishizawa and Colleagues have found that BACH1 promotes ferroptosis by inhibiting the expression of genes for iron metabolism and those for glutathione synthesis. Furthermore, we found that BACCH1-regulated ferroptosis is involved in the pathophysiology of cardiac infarction. One of the data was featured in the cover page of JBC issue.
Nishizawa H. et al, Ferroptosis is controlled by the coordinated transcriptional regulation of glutathione and labile iron metabolism by the transcription factor BACH1. J. Biol. Chem. 295, 69-, 2020
Regulation of inner myeloid by BACH
To be red or white: lineage commitment and maintenance of the hematopoietic system by the "inner myeloid" 20191108
Based on recent reports on hematopiesis using RNA-sequence analysis, we summarized the pathways of hematopoietic cell differentiation and emerging new problems. We discuss how to understand gene regulatory network underlying differentiation of diverse types of cells based on myeloid cell differentiation as a default pathway. We then discuss repression of myeloid genes by BACH transcription factors.
Kato H and Igarashi K, To be red or white: lineage commitment and maintenance of the hematopoietic system by the "inner myeloid", Haematologica 104, 1919-, 2019
Regulation of BACH1 by heme
COLLABORATIVE PAPER IS OUT, 20190528
Heme oxygenase-1 (HO-1) is induced in response to infection to protect cells and tissues from infectious stresses. We show in this paper that LPS binds to Toll-like receptor to increase intracellular labile (fee) heme, which then binds to BACH1 and inactivates its regulatory activity, leading to up-regulation of HO-1 expression. Thus, a signaling function of labile heme is becoming clearer.
This is a collaboration with Prof. Stephan Immenschuh, Hanover Medical School, Germany, and Dr. Roberto Motterlini, IMRB, France.
Sudan, K., Vijayan, V., Madyaningrana, K., Gueler, F., Igarashi, K., Foresti, R., Motterlini, R. and Immenschuh, S. TLR4 activation alters labile heme levels to regulate BACH1 and heme oxygenase-1 expression in macrophages. Free Radic. Biol. Med. In press (2019)
Regulation of BACH1 by heme
COLLABORATIVE PAPER IS OUT, 20190528
BACH1 possesses 6 cystein-proline (CP) motifs which mediate 5-cooridation binding to heme. This paper is on heme binding to the 6th CP motif. This CP motif is within disordered structure region. Upon heme binding, this region remains disordered, but the state is different from when it is not bound by heme. Thus heme regulate the function of BACH1 by promoting disordered-disordered structure transition.
This study is a collaboration with Dr. Kazutaka Murayama, School of Medical Engeneering, and Kei Segawa, Teijin Pharma.
Segawa, K., Watanabe-Matsui, M., Matsui, T., Igarashi, K. and Murayama, K. Functional Heme Binding to the Intrinsically Disordered C-Terminal Region of Bach1, a Transcriptional Repressor. Tohoku J. Exp. Med. 247, 153-159 (2019)
Regulation of BACH1 by heme
COLLABORATIVE PAPER IS OUT, 20190528
BACH1 is inactivated as a transcription factor uponn direct binding of prosthetic group heme. BACH1 possesses six cystein-proline (CP) motifs each can mediate heme binding. In this paper, we analyzed three of the CP motifs upstream of the DNA binding domain using various biophysical measurements. These CP motifs are in disordered structure, which remained disordered upon heme binding. However, heme binding altered intra-molecular interaction of BACH1, which may be important for the regulation of its activity. Signaling function of heme is becoming clearer.
This study is a collaboration with Dr. Kazutaka Murayama, School of Medical Engeneering, and Kei Segawa, Teijin Pharma.
Segawa, K., Watanabe-Matsui, M., Tsuda, K., Matsui, T., Shirouzu, M., Igarashi, K. and Murayama, K. Biophysical characterization of heme binding to the intrinsically disordered region of Bach1. Eur. Biophys. J. in press (2019)
Identification of new TOR target in Algae
COLLABORATIVE PAPER IS OUT, 20190528
Cyanidioschyzon merolae belongs to monocelular algae and is gathering interest as a source of biofule. Inhibition of TOR signaling cascade leads to upregulation of starch content but the mechanism of this response has been elusive. In this paper, we carried out phosphoproteome analysis using mass spectrometry and found phosphorylation of many proteins in starch synthes by TOR pathway.
This paper is a collaboration with Dr. Sousuke Imamura, Tokyo Institute of Technology, and Dr. Atsushi Higashitani, Graduate School of Life Science, Tohoku University. Dr. Hiroki Shima carried out mass spectrometry analysis.
Pancha, I., Shima, H., Higashitani, N., Igarashi, K., Higashitani, A., Tanaka, K. and Imamura, S. Target of rapamycin (TOR) signaling modulates starch accumulation via glycogenin phosphorylation status in the unicellular red alga Cyanidioschyzon merolae. Plant J. 97, 485-499 (2019)
Fate decision mechanism of hematopoietic stem and progenitor cells
We showed previously that BACH1 and BACH2 promote lymphoid cell development by suppressing myeloid program of gene expression in progenitor cells. In this study, we discovered that BACH1 and BACH2 represses myeloid program to promote erythroid commitment in stem and progenitor cells. Their function is reduced upon infection in part by heme, erythroid cell development is reduced under such circumstances. This may explain the disease process of anemia of infection. We also found that BACH2 expression is reduced in myelodysplastic syndrome, possibly accounting for anemia or immunodeficiency.
Derangement of gene regulatory network involving BACH1 and BACH2 may contribute anemia of vaious diseases.
This study is led by Dr. Hiroki Kato in a collaboration with Prof. Hideo Harigae, Department of Hematology ad Rheumatology, Prof. Seishi Ogawa, Kyoto University, and Prof. Mario Cazzola, University of Pavia, Italy.
Kato, H., Itoh-Nakadai, A., Matsumoto, M., Ishii, Y., Watanabe-Matsui, M., Ikeda, M., Ebina-Shibuya, R., Sato, Y., Kobayashi, M., Nishizawa, H., Suzuki, K., Muto, A., Fujiwara, T., Nannya, Y., Malcovati, L., Cazzola, M., Ogawa, S., Harigae, H. and Igarashi, K. Infection perturbs Bach2- and Bach1-dependent erythroid lineage ‘choice’ to cause anemia. Nature Immunol. 19, 1059-1070 (2018)
