The Experts below are selected from a list of 50778 Experts worldwide ranked by ideXlab platform
Kazuhiko Igarashi - One of the best experts on this subject based on the ideXlab platform.
-
the transcription factor BACH1 at the crossroads of cancer biology from epithelial mesenchymal transition to ferroptosis
Journal of Biological Chemistry, 2021Co-Authors: Kazuhiko Igarashi, Hironari Nishizawa, Yuriko Saiki, Mitsuyo MatsumotoAbstract:The progression of cancer involves not only the gradual evolution of cells by mutations in DNA but also alterations in the gene expression induced by those mutations and input from the surrounding microenvironment. Such alterations contribute to cancer cells' abilities to reprogram metabolic pathways and undergo epithelial-to-mesenchymal transition (EMT), which facilitate the survival of cancer cells and their metastasis to other organs. Recently, BTB and CNC homology 1 (BACH1), a heme-regulated transcription factor that represses genes involved in iron and heme metabolism in normal cells, was shown to shape the metabolism and metastatic potential of cancer cells. The growing list of BACH1 target genes in cancer cells reveals that BACH1 promotes metastasis by regulating various sets of genes beyond iron metabolism. BACH1 represses the expression of genes that mediate cell-cell adhesion and oxidative phosphorylation but activates the expression of genes required for glycolysis, cell motility, and matrix protein degradation. Furthermore, BACH1 represses FOXA1 gene encoding an activator of epithelial genes and activates SNAI2 encoding a repressor of epithelial genes, forming a feedforward loop of EMT. By synthesizing these observations, we propose a "two-faced BACH1 model", which accounts for the dynamic switching between metastasis and stress resistance along with cancer progression. We discuss here the possibility that BACH1-mediated promotion of cancer also brings increased sensitivity to iron-dependent cell death (ferroptosis) through crosstalk of BACH1 target genes, imposing programmed vulnerability upon cancer cells. We also discuss the future directions of this field, including the dynamics and plasticity of EMT.
-
BACH1 plays an important role in angiogenesis through regulation of oxidative stress
Microvascular Research, 2021Co-Authors: Farina Mohamad Yusoff, Satoshi Tashiro, Kazuhiko Igarashi, Kazuaki Chayama, Tatsuya Maruhashi, Ki Ichiro Kawano, Ayumu Nakashima, Yukihito HigashiAbstract:BACH1 is a known transcriptional repressor of the heme oxygenase-1 (HO-1) gene. The purpose of this study was to determine whether angiogenesis is accelerated by genetic ablation of BACH1 in a mouse ischemic hindlimb model. Hindlimb ischemia was surgically induced in wild-type (WT) mice, BACH1-deficient (BACH1-/-) mice, apolipoprotein E-deficient (ApoE-/-) mice, and BACH1/ApoE double-knockout (BACH1-/-/ApoE-/-) mice. Blood flow recovery after hindlimb ischemia showed significant improvement in BACH1-/- mice compared with that in WT mice. BACH1-/-/ApoE-/- mice showed significantly improved blood flow recovery compared with that in ApoE-/- mice to the level of that in WT mice. Migration of endothelial cells in ApoE-/- mice was significantly decreased compared with that in WT mice. Migration of endothelial cells significantly increased in BACH1-/-/ApoE-/- mice compared with that in ApoE-/- mice to the level of that in WT mice. The expression levels of HO-1, peroxisome proliferator-activated receptor γ co-activator-1α, angiopoietin 1, and fibroblast growth factor 2 in endothelial cells isolated from BACH1-/-/ApoE-/- mice were significantly higher than those in ApoE-/- mice. Oxidative stress assessed by anti-acrolein antibody staining in ischemic tissues and urinary 8-isoPGF2α excretion were significantly increased in ApoE-/- mice compared with those in WT and BACH1-/- mice. Oxidative stress was reduced in BACH1-/-/ApoE-/- mice compared with that in ApoE-/- mice. These findings suggest that genetic ablation of BACH1 plays an important role in ischemia-induced angiogenesis under the condition of increased oxidative stress. BACH1 could be a potential therapeutic target to reduce oxidative stress and potentially improve angiogenesis for patients with peripheral arterial disease.
-
BACH1 promotes muscle regeneration through repressing Smad-mediated inhibition of myoblast differentiation.
PLOS ONE, 2020Co-Authors: Katsushi Suzuki, Mitsuyo Matsumoto, Yasutake Katoh, Liang Liu, Kyoko Ochiai, Yuta Aizawa, Ryoichi Nagatomi, Hiroshi Okuno, Eiji Itoi, Kazuhiko IgarashiAbstract:It has been reported that BACH1-deficient mice show reduced tissue injuries in diverse disease models due to increased expression of heme oxygenase-1 (HO-1)that possesses an antioxidant function. In contrast, we found that BACH1 deficiency in mice exacerbated skeletal muscle injury induced by cardiotoxin. Inhibition of BACH1 expression in C2C12 myoblast cells using RNA interference resulted in reduced proliferation, myotube formation, and myogenin expression compared with control cells. While the expression of HO-1 was increased by BACH1 silencing in C2C12 cells, the reduced myotube formation was not rescued by HO-1 inhibition. Up-regulations of Smad2, Smad3 and FoxO1, known inhibitors of muscle cell differentiation, were observed in BACH1-deficient mice and BACH1-silenced C2C12 cells. Therefore, BACH1 may promote regeneration of muscle by increasing proliferation and differentiation of myoblasts.
-
tlr4 activation alters labile heme levels to regulate BACH1 and heme oxygenase 1 expression in macrophages
Free Radical Biology and Medicine, 2019Co-Authors: Kritika Sudan, Kazuhiko Igarashi, Vijith Vijayan, Kukuh Madyaningrana, Faikah Gueler, Roberta Foresti, Roberto Motterlini, Stephan ImmenschuhAbstract:Heme oxygenase (HO)-1, a stress-inducible enzyme that converts heme into carbon monoxide (CO), iron and biliverdin, exerts important anti-inflammatory effects in activated macrophages. HO-1 expression is mainly governed by a mutual interplay between the transcriptional factor NRF2 and the nuclear repressor BTB and CNC homology 1 (BACH1), a heme sensor protein. In the current study we hypothesized that alterations in the levels of intracellular labile heme in macrophages stimulated by lipopolysaccharide (LPS), a prototypical pro-inflammatory Toll-like receptor (TLR)4 agonist, are responsible for BACH1-dependent HO-1 expression. To this end, labile heme was determined in both mouse bone marrow-derived macrophages (mBMDMs) and human monocyte-derived macrophages (hMDMs) using an apo-horseradish peroxidase-based assay. We found that LPS raised the levels of labile heme, depressed BACH1 protein and up-regulated HO-1 in mBMDMs. In contrast, in hMDMs LPS decreased labile heme levels while increasing BACH1 expression and down-regulating HO-1. These effects were abolished by the TLR4 antagonist TAK-242, suggesting that TLR4 activation triggers the signaling cascade leading to changes in the labile heme pool. Studies using mBMDMs from BACH1-/- and NRF2-/- mice revealed that regulation of HO-1 and levels of labile heme after LPS stimulation are strictly dependent on BACH1, but not NRF2. A strong interplay between BACH1-mediated HO-1 expression and intracellular levels of labile heme was also confirmed in hMDMs with siRNA knockdown studies and following inhibition of de novo heme synthesis with succinylacetone. Finally, CORM-401, a compound that liberates CO, counteracted LPS-dependent down-regulation of HO-1 and restored levels of labile heme in hMDMs. In conclusion, alterations of labile heme levels in macrophages following TLR4 stimulation play a crucial role in BACH1-mediated regulation of HO-1 expression.
-
Biophysical characterization of heme binding to the intrinsically disordered region of BACH1.
European Biophysics Journal, 2019Co-Authors: Kei Segawa, Kazuhiko Igarashi, Miki Watanabe-matsui, Toshitaka Matsui, Kengo Tsuda, Mikako Shirouzu, Kazutaka MurayamaAbstract:Transcriptional repressor BACH1 plays an important role in antioxidant response. BACH1 function is regulated by heme binding to the four cysteine-proline (CP) motifs in BACH1, which leads to inhibition of its activity. Three of these CP motifs are located N-terminal to the bZip (basic leucine zipper) domain that is responsible for DNA binding. Based on sequence analysis, the region surrounding these CP motifs was expected to be intrinsically disordered. BACH1 is one of few known intrinsically disordered proteins that accept multiple heme molecules for functional regulation, but the molecular mechanisms of heme binding and functional regulation remain unclear. Uncovering these mechanisms is important for understanding BACH1-mediated antioxidant response. Biophysical characterization revealed that 5-coordinated heme binding was unique to the CP motifs within the heme-binding region of BACH1, whereas 6-coordinated binding occurred nonspecifically. Comparison of the wild-type protein and a CP motif mutant indicated that the level of 6-coordinated heme binding was reduced in the absence of 5-coordinated heme binding. Analytical ultracentrifugation showed that the CP motif mutant protein had a more elongated conformation than the wild-type protein, suggesting that cysteines within the CP motifs contribute to intramolecular interactions in BACH1. Thus, heme binding at the CP motifs induces a global conformational change in the BACH1 heme-binding region, and this conformational change, in turn, regulates the biological activity of BACH1.
Mitsuyo Matsumoto - One of the best experts on this subject based on the ideXlab platform.
-
the transcription factor BACH1 at the crossroads of cancer biology from epithelial mesenchymal transition to ferroptosis
Journal of Biological Chemistry, 2021Co-Authors: Kazuhiko Igarashi, Hironari Nishizawa, Yuriko Saiki, Mitsuyo MatsumotoAbstract:The progression of cancer involves not only the gradual evolution of cells by mutations in DNA but also alterations in the gene expression induced by those mutations and input from the surrounding microenvironment. Such alterations contribute to cancer cells' abilities to reprogram metabolic pathways and undergo epithelial-to-mesenchymal transition (EMT), which facilitate the survival of cancer cells and their metastasis to other organs. Recently, BTB and CNC homology 1 (BACH1), a heme-regulated transcription factor that represses genes involved in iron and heme metabolism in normal cells, was shown to shape the metabolism and metastatic potential of cancer cells. The growing list of BACH1 target genes in cancer cells reveals that BACH1 promotes metastasis by regulating various sets of genes beyond iron metabolism. BACH1 represses the expression of genes that mediate cell-cell adhesion and oxidative phosphorylation but activates the expression of genes required for glycolysis, cell motility, and matrix protein degradation. Furthermore, BACH1 represses FOXA1 gene encoding an activator of epithelial genes and activates SNAI2 encoding a repressor of epithelial genes, forming a feedforward loop of EMT. By synthesizing these observations, we propose a "two-faced BACH1 model", which accounts for the dynamic switching between metastasis and stress resistance along with cancer progression. We discuss here the possibility that BACH1-mediated promotion of cancer also brings increased sensitivity to iron-dependent cell death (ferroptosis) through crosstalk of BACH1 target genes, imposing programmed vulnerability upon cancer cells. We also discuss the future directions of this field, including the dynamics and plasticity of EMT.
-
BACH1 promotes muscle regeneration through repressing Smad-mediated inhibition of myoblast differentiation.
PLOS ONE, 2020Co-Authors: Katsushi Suzuki, Mitsuyo Matsumoto, Yasutake Katoh, Liang Liu, Kyoko Ochiai, Yuta Aizawa, Ryoichi Nagatomi, Hiroshi Okuno, Eiji Itoi, Kazuhiko IgarashiAbstract:It has been reported that BACH1-deficient mice show reduced tissue injuries in diverse disease models due to increased expression of heme oxygenase-1 (HO-1)that possesses an antioxidant function. In contrast, we found that BACH1 deficiency in mice exacerbated skeletal muscle injury induced by cardiotoxin. Inhibition of BACH1 expression in C2C12 myoblast cells using RNA interference resulted in reduced proliferation, myotube formation, and myogenin expression compared with control cells. While the expression of HO-1 was increased by BACH1 silencing in C2C12 cells, the reduced myotube formation was not rescued by HO-1 inhibition. Up-regulations of Smad2, Smad3 and FoxO1, known inhibitors of muscle cell differentiation, were observed in BACH1-deficient mice and BACH1-silenced C2C12 cells. Therefore, BACH1 may promote regeneration of muscle by increasing proliferation and differentiation of myoblasts.
-
BACH1 Promotes Pancreatic Cancer Metastasis by Repressing Epithelial Genes and Enhancing Epithelial-Mesenchymal Transition.
Cancer Research, 2020Co-Authors: Masaki Sato, Mitsuyo Matsumoto, Andrey Brydun, Hironari Nishizawa, Yuriko Saiki, Mahabub Alam, Masahiro Rokugo, Shinji Yamada, Mika K. Kaneko, Ryo FunayamaAbstract:Pancreatic ductal adenocarcinoma (PDAC) is among the cancers with the poorest prognoses due to its highly malignant features. BTB and CNC homology 1 (BACH1) has been implicated in RAS-driven tumor formation. We focused on the role of BACH1 in PDAC, more than 90% of which have KRAS mutation. Knockdown of BACH1 in PDAC cell lines reduced cell migration and invasion, in part, by increasing E-cadherin expression, whereas its overexpression showed opposite effects. BACH1 directly repressed the expression of FOXA1 that is known to activate the expression of CDH1 encoding E-cadherin and to inhibit epithelial-to-mesenchymal transition. BACH1 also directly repressed the expression of genes important for epithelial cell adhesion including CLDN3 and CLDN4. In a mouse orthotopic implantation model, BACH1 was required for the high metastatic ability of AsPC-1 cells. IHC analysis of clinical specimens with a newly developed anti-BACH1 mAb revealed that high expression of BACH1 is a poor prognostic factor. These results suggest that the gene regulatory network of BACH1 and downstream genes including CDH1 contribute to the malignant features of PDAC by regulating epithelial-to-mesenchymal transition. SIGNIFICANCE: Greater understanding of the gene regulatory network involved in epithelial-to-mesenchymal transition of pancreatic cancer cells will provide novel therapeutic targets and diagnostic markers.
-
infection perturbs bach2 and BACH1 dependent erythroid lineage choice to cause anemia
Nature Immunology, 2018Co-Authors: Hiroki Kato, Ari Itohnakadai, Mitsuyo Matsumoto, Risa Ebinashibuya, Yusho Ishii, Miki Watanabematsui, Masatoshi Ikeda, Yuki SatoAbstract: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.
-
Phosphorylation of BACH1 switches its function from transcription factor to mitotic chromosome regulator and promotes its interaction with HMMR.
Biochemical Journal, 2018Co-Authors: Hiroki Shima, Hiroki Kato, Mitsuyo Matsumoto, Masatoshi Ikeda, Andrey Brydun, Hironari Nishizawa, Yuriko Saiki, Liang Liu, Miki Watanabe-matsuiAbstract:The transcription repressor BACH1 performs mutually independent dual roles in transcription regulation and chromosome alignment during mitosis by supporting polar ejection force of mitotic spindle. We now found that the mitotic spindles became oblique relative to the adhesion surface following endogenous BACH1 depletion in HeLa cells. This spindle orientation rearrangement was rescued by re-expression of BACH1 depending on its interactions with HMMR and CRM1, both of which are required for the positioning of mitotic spindle, but independently of its DNA-binding activity. A mass spectrometry analysis of BACH1 complexes in interphase and M phase revealed that BACH1 lost during mitosis interactions with proteins involved in chromatin and gene expression but retained interactions with HMMR and its known partners including CHICA. By analyzing BACH1 modification using stable isotope labeling with amino acids in cell culture, mitosis-specific phosphorylations of BACH1 were observed, and mutations of these residues abolished the activity of BACH1 to restore mitotic spindle orientation in knockdown cells and to interact with HMMR. Detailed histological analysis of BACH1-deficient mice revealed lengthening of the epithelial fold structures of the intestine. These observations suggest that BACH1 performs stabilization of mitotic spindle orientation together with HMMR and CRM1 in mitosis, and that the cell cycle-specific phosphorylation switches the transcriptional and mitotic functions of BACH1.
Akihiko Muto - One of the best experts on this subject based on the ideXlab platform.
-
Iron-heme-BACH1 axis is involved in erythroblast adaptation to iron deficiency
Haematologica, 2016Co-Authors: Masahiro Kobayashi, Akihiko Muto, Hiroki Kato, Tohru Fujiwara, Ari Itoh-nakadai, Hiroshi Hada, Yukihiro Inoguchi, Kenji Ichiyanagi, Wataru Hojo, Naohisa TomosugiAbstract: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.
-
transcription factor BACH1 and bach2 operate erythro myeloid competitive differentiation by responding to environmental changes
Blood, 2016Co-Authors: Hiroki Kato, Akihiko Muto, Ari Itohnakadai, Mitsuyo Matsumoto, Risa Ebinashibuya, Yuki Sato, Masahiro Kobayashi, Tohru Fujiwara, Hideo Harigae, Kazuhiko IgarashiAbstract:Hematopoietic system is maintained by the differentiation and proliferation of hematopoietic stem/progenitor cells (HSPCs) and their commitment to the mature blood cells should be tightly controlled by gene regulatory networks (GRNs) governed by transcription factors (TFs). To keep the homeostasis, GRNs should respond to the environmental changes, such as infection. However, the precise mechanism of such a system remains to be elucidated. TFs BACH1 and Bach2 belong to the basic region-leucine zipper family and recognize Maf-recognition elements containing AP-1 site (Oyake et al., 1996). We have previously shown that BACH1 -/- Bach2 -/- (DKO; double knockout) mice show erythropoiesis disorders with increased myelopoiesis from common myeloid progenitors (CMPs), which is an erythro-myeloid bifurcation point (ASH2015; Abstract ID# 81562) (Akashi et al., 2000). Since this phenotype is similar to that of LPS treated mice (O9Connell et al., 2008), we hypothesized that Bach factors work as sensors for infection. First, to evaluate the cell-intrinsic function of Bach factors, WT or DKO bone marrow cells were depleted of mature differentiated cells and transplanted to lethally irradiated WT mice. After 8 weeks, DKO donor cells showed greater myelopoiesis and lesser lymphogenesis compared to WT, suggesting Bach factors are necessary to suppress myelopoiesis to the appropriate level in regenerating hematopoiesis. To reveals the function of Bach factors in HSPCs from other aspect, LSKs (Lin - Sca1 + c-kit + ) were infected with retroviruses expressing BACH1-IRES-eGFP or Bach2-IRES-eGFP and transplanted to lethally irradiated WT mice. Cells derived from transgene induced LSKs were monitored by GFP fluorescence. After 2 weeks, BACH1 overexpressing LSKs did not show any difference in erythropoiesis and myelopoiesis. This might be explained by the high BACH1 expression levels in HSPCs according to the previous report (Lara-Astiaso et al., 2014). On the other hand, Bach2 overexpressing LSKs showed increased erythropoiesis and decreased myelopoiesis, suggesting that Bach2 regulates the erythro-myeloid lineage specification as expected by the observations of DKO mice. To assess the function of Bach factors under infection, we used M1 murine myeloid leukemia cells that differentiate to macrophage-like cells by LPS stimulation. LPS stimulation reduced expressions of BACH1 , Bach2 and erythroid gene Gata1 , and induced those of myeloid genes such as Cebpb and Csf1r in a dose-dependent manner. To determine if down-regulation of Bach factors is necessary for myeloid differentiation, BACH1 or Bach2 were transgenically overexpressed in M1 cells. Both of the M1 cells overexpressing BACH1 or Bach2 showed lower expression levels of myeloid marker CD11b compared to control under LPS stimulation. Thus, reductions of the expression of Bach factors in response to LPS were necessary for appropriate myeloid differentiation. To identify the direct target genes of Bach factors, BACH1 or Bach2 ChIP-seq data of M1 cells (Ebina-Shibuya et al., 2016) were merged with results of expression profile of WT and DKO CMPs. Several myeloid or inflammatory genes such as Cebpb , Fcgr1 and Tlr4 were identified as putative repressed target genes and several erythroid or lymphoid genes such as Klf1 , Rag1 and Rag2 were identified as putative activated target genes. In addition, when BACH1 or Bach2 ChIP-seq data were merged by that of C/EBPb, which also possesses AP-1 site as its target motif, obtained from ENCODE database (ENCSR000AIB), we found that there were several co-localized regions of Bach and C/EBPb near the myeloid genes such as Cebpa , Il6 and Fcgr1 . These observations suggest that Bach factors repress myeloid genes by competitively working with C/EBPb at same genomic regions. This is particularly interesting in the light of the latest findings showing the Bach2 function on AP-1 site in lymphoid cells (Sidwell et al., 2016). These results reveal a novel mechanism by which how the differentiation of erythro-myeloid bifurcation is controlled by responding to environmental changes. Bach factors regulate erythro-myeloid competitive differentiation by promoting and repressing erythroid and myeloid differentiation, respectively. We suggest that infection promote myelopoiesis at the expense of erythropoiesis by reducing the expression of Bach factors. Therefore, Bach factors may function as sensors for environmental changes. Disclosures No relevant conflicts of interest to declare.
-
the double knockout of BACH1 and bach2 in mice reveals shared compensatory mechanisms in regulating alveolar macrophage function and lung surfactant homeostasis
Journal of Biochemistry, 2016Co-Authors: Risa Ebinashibuya, Kazuhiko Igarashi, Akihiko Muto, Ari Itohnakadai, Mitsuyo Matsumoto, Miki Watanabematsui, Ryo Funayama, Keiko NakayamaAbstract:Pulmonary alveolar proteinosis (PAP) is a disease resulting from a dysfunction of the alveolar macrophages (AMs) where excess surfactant protein accumulates in the alveolar spaces. We previously reported that Bach2 KO mice developed PAP due to a defect in the handling of lipids by AMs. To investigate the functions of BACH1 and Bach2, which are regulated by oxidative stress, in the AMs and in lung homeostasis, we generated mice that lacked both BACH1 and Bach2 (BACH1/2 DKO mice). The BACH1/2 DKO mice showed more severe PAP phenotype than Bach2 KO mice with abnormal AMs, whereas the BACH1 KO mice did not develop any pulmonary disease. The PAP-like disease in the BACH1/2 DKO and Bach2 KO mice was not ameliorated by antioxidant, suggesting that ROS was not involved in the onset of PAP in the absence of BACH1 and Bach2. A microarray and a chromatin immunoprecipitation sequence analysis revealed that BACH1 and Bach2 directly repress the common set of genes involved in the inflammatory response, and that Bach2 is a major contributor to this repression. These results suggest that BACH1 and Bach2 work in a complementary manner to maintain the normal function of the AMs and surfactant homeostasis in the lung.
-
transcription factor BACH1 and bach2 control common myeloid progenitor cell differentiation under infectious stimuli
Blood, 2015Co-Authors: Hiroki Kato, Akihiko Muto, Ari Itohnakadai, Mitsuyo Matsumoto, Risa Ebinashibuya, Masahiro Kobayashi, Tohru Fujiwara, Hideo Harigae, Kazuhiko IgarashiAbstract:Background: Erythrocyte and granulocyte/macrophage develop from common myeloid progenitor (CMP) (Akashi et al., 2000). Differentiation of hematopoietic progenitor cells is precisely controlled by multiple transcription factors, among which GATA1, C/EBPα, C/EBPβ and Spi-C play pivotal roles in erythrocyte and granulocyte/macrophage differentiation (Mancini et al., 2012; Pongubala et al., 2008; Hirai et al., 2006; Haldar et al., 2014). However, the mechanism by which the differentiation of CMP controlled under infectious condition has been unclear. BACH1 and Bach2 belong to the basic region-leucine zipper family and recognize Maf-recognition elements (Oyake et al., 1996). They promote B cell development by repressing the myeloid genes such as Cebpb and Spic in common lymphoid progenitor cells (Itoh-Nakadai et al., 2014). In addition, BACH1 regulates several target genes related to iron/heme homeostasis such as globin genes and hemeoxygenase-1, and Bach2 may similarly regulate these genes (Igarashi, 2014). Therefore, it is expected that both BACH1 and Bach2 play redundant roles in erythropoiesis. To figure out their roles in erythroid and myeloid cell differentiation, we performed hematological and transcriptomics analyses using BACH1-/- Bach2-/- (double-deficient; DD) mice. Methods: The generation of DD mice on the C57BL/6J background and Bach2 reporter mice with red fluorescent protein coding cDNA inserted in the Bach2 locus were described previously (Itoh-Nakadai et al., 2014). Mice between 8-12 weeks old were analyzed in the present study. Bone marrow (BM) cells were stained with specific combinations of antibodies to identify erythroid/myeloid progenitor and mature cells (Sheila et al., 2008; Cornelis et al., 2007; Socolovsky et al., 2001). Flow cytometry analysis and cell sorting were performed by using FACSAriaⅡ(BD) and FlowJo software (TreeStar). For infectious simulation of CMP, sorted CMPs were incubated with 1μg/ml LPS (Sigma) for 48h and RNA was purified with RNeasy micro kit (Qiagen). Quantitative PCR by using SuperscriptⅢ reverse transcriptase (Invitrogen) and Light Cycler system (Roche) was performed according to manufacturer9s instructions. Microarray analysis by using Sure-Print G3 mouse GE microarray slide (Agilent) was performed as previously described (Itoh-Nakadai et al., 2014) and the results were analyzed by using GeneSpring software (Agilent). We used Gene Set Enrichment Analysis (GSEA) to interpret gene expression data (Subramanian et al., 2005; Mootha et al., 2003). LPS stimulation (50 μg/body) of mice was performed as previously described (Ryan et al., 2008). Data were analyzed by the two-sided Student9s t-test and p - values of Results: DD mice show mild normocytic anemia compered to wild-type (WT), BACH1-/-, and Bach2-/- mice (hemoglobin; 14.4±0.2, 14.0±0.3, 13.5±0.3 and 11.9±0.7 g/dl, for WT, BACH1-/-, Bach2-/- and DD, respectively, p Conclusions: BACH1 and Bach2 control the differentiation of CMP to erythroid cell or myeloid cell by repressing myeloid genes such as Cebpb and Spic. Infectious stimuli may promote myeloid cell differentiation by reducing the expression of BACH1 and Bach2 in CMP. Disclosures Fujiwara:Chugai Pharmaceutical CO., LTD: Research Funding. Harigae:Chugai Pharmaceutical CO., LTD: Research Funding.
-
the transcription repressors bach2 and BACH1 promote b cell development by repressing the myeloid program
Nature Immunology, 2014Co-Authors: Ari Itohnakadai, Akihiko Muto, Yuki Sato, Masahiro Kobayashi, Miki Watanabematsui, Reina Hikota, Kohei Kometani, Atsushi Nakamura, Yuichi Miura, Yoko YanoAbstract:Mature lymphoid cells express the transcription repressor Bach2, which imposes regulation on humoral and cellular immunity. Here we found critical roles for Bach2 in the development of cells of the B lineage, commencing from the common lymphoid progenitor (CLP) stage, with BACH1 as an auxiliary. Overexpression of Bach2 in pre-pro-B cells deficient in the transcription factor EBF1 and single-cell analysis of CLPs revealed that Bach2 and BACH1 repressed the expression of genes important for myeloid cells ('myeloid genes'). Bach2 and BACH1 bound to presumptive regulatory regions of the myeloid genes. Bach2(hi) CLPs showed resistance to myeloid differentiation even when cultured under myeloid conditions. Our results suggest that Bach2 functions with BACH1 and EBF1 to promote B cell development by repressing myeloid genes in CLPs.
Jiying Sun - One of the best experts on this subject based on the ideXlab platform.
-
BACH1 Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice
Oxidative Medicine and Cellular Longevity, 2014Co-Authors: Kazushige Ota, Andrey Brydun, Jiying Sun, Ari Itoh-nakadai, Kazuhiko IgarashiAbstract:Oxidative stress contributes to both aging and tumorigenesis. The transcription factor BACH1, a regulator of oxidative stress response, augments oxidative stress by repressing the expression of heme oxygenase-1 (HO-1) gene (Hmox1) and suppresses oxidative stress-induced cellular senescence by restricting the p53 transcriptional activity. Here we investigated the lifelong effects of BACH1 deficiency on mice. BACH1-deficient mice showed longevity similar to wild-type mice. Although HO-1 was upregulated in the cells of BACH1-deficient animals, the levels of ROS in BACH1-deficient HSCs were comparable to those in wild-type cells. BACH1−/−; p53−/− mice succumbed to spontaneous cancers as frequently as p53-deficient mice. BACH1 deficiency significantly altered transcriptome in the liver of the young mice, which surprisingly became similar to that of wild-type mice during the course of aging. The transcriptome adaptation to BACH1 deficiency may reflect how oxidative stress response is tuned upon genetic and environmental perturbations. We concluded that BACH1 deficiency and accompanying overexpression of HO-1 did not influence aging or p53 deficiency-driven tumorigenesis. Our results suggest that it is useful to target BACH1 for acute injury responses without inducing any apparent deteriorative effect.
-
heme positively regulates the expression of β globin at the locus control region via the transcriptional factor BACH1 in erythroid cells
Biochemical and Biophysical Research Communications, 2004Co-Authors: Tsuyoshi Tahara, Kazuhiko Igarashi, Jiying Sun, Shigeru TaketaniAbstract:Abstract The transcriptional factor BACH1 forms a heterodimer with small Maf family, and functions as a repressor of the Maf recognition element (MARE) in vivo. To investigate the involvement of BACH1 in the heme-dependent regulation of the expression of the α-globin gene, human erythroleukemia K562 cells were cultured with succinylacetone (SA), a heme biosynthetic inhibitor, and the level of α-globin mRNA was examined. A decrease of α-globin mRNA was observed in SA-treated cells, which was restored by the addition of hemin. The heme-dependent expression of α-globin occurred at the transcriptional level since the expression of human α-globin gene promoter–reporter gene containing hypersensitive site-40 (HS-40) was decreased when K562 cells were cultured with SA. Hemin treatment restored the decrease of the promoter activity by SA. The regulation of the HS-40 activity by heme was dependent on the NF-E2/AP-1 (NA) site, which is similar to MARE. The NA site-binding activity of BACH1 in K562 increased upon SA-treatment, and the increase was diminished by the addition of hemin. The transient expression of BACH1 and mutated BACH1 lacking CP motifs suppressed the HS-40 activity, and cancellation of the repressor activity by hemin was observed when wild-type BACH1 was expressed. The expression of NF-E2 strengthened the restoration of the BACH1-effect by hemin. Interestingly, nuclear localization of BACH1 increased when cells were treated with SA, while hemin induced the nuclear export of BACH1. These results indicated that heme plays an important role in the induction of α-globin gene expression through disrupting the interaction of BACH1 and the NA site in HS-40 enhancer in erythroid cells.
-
heme dependent up regulation of the α globin gene expression by transcriptional repressor BACH1 in erythroid cells
Biochemical and Biophysical Research Communications, 2004Co-Authors: Tsuyoshi Tahara, Kazuhiko Igarashi, Jiying Sun, Shigeru TaketaniAbstract:Abstract The transcriptional factor BACH1 forms a heterodimer with small Maf family, and functions as a repressor of the Maf recognition element (MARE) in vivo. To investigate the involvement of BACH1 in the heme-dependent regulation of the expression of the α-globin gene, human erythroleukemia K562 cells were cultured with succinylacetone (SA), a heme biosynthetic inhibitor, and the level of α-globin mRNA was examined. A decrease of α-globin mRNA was observed in SA-treated cells, which was restored by the addition of hemin. The heme-dependent expression of α-globin occurred at the transcriptional level since the expression of human α-globin gene promoter–reporter gene containing hypersensitive site-40 (HS-40) was decreased when K562 cells were cultured with SA. Hemin treatment restored the decrease of the promoter activity by SA. The regulation of the HS-40 activity by heme was dependent on the NF-E2/AP-1 (NA) site, which is similar to MARE. The NA site-binding activity of BACH1 in K562 increased upon SA-treatment, and the increase was diminished by the addition of hemin. The transient expression of BACH1 and mutated BACH1 lacking CP motifs suppressed the HS-40 activity, and cancellation of the repressor activity by hemin was observed when wild-type BACH1 was expressed. The expression of NF-E2 strengthened the restoration of the BACH1-effect by hemin. Interestingly, nuclear localization of BACH1 increased when cells were treated with SA, while hemin induced the nuclear export of BACH1. These results indicated that heme plays an important role in the induction of α-globin gene expression through disrupting the interaction of BACH1 and the NA site in HS-40 enhancer in erythroid cells.
-
heme regulates gene expression by triggering crm1 dependent nuclear export of BACH1
The EMBO Journal, 2004Co-Authors: Hiroshi Suzuki, Satoshi Tashiro, Jiying Sun, Shusuke Hira, Chikara Yamazaki, Yukari Zenke, Minoru Yoshida, Masao Ikedasaito, Kazuhiko IgarashiAbstract:BACH1 is a transcriptional repressor of heme oxygenase-1 and β-globin genes, both of which are known to be transcriptionally induced by heme. To test the hypothesis that heme regulates the activity of BACH1, we expressed wild type and mutated versions of BACH1 together with or without its heterodimer partner MafK in human 293T and GM02063 cells and examined their subcellular localization. Inhibition of heme synthesis enhanced the nuclear accumulation of BACH1, whereas treating cells with hemin resulted in nuclear exclusion of BACH1. While the cadmium-inducible nuclear export signal (NES) of BACH1 was dispensable for the heme response, a region containing two of the heme-binding motifs was found to be critical for the heme-induced nuclear exclusion. This region functioned as a heme-regulated NES dependent on the exporter Crm1. These results extend the regulatory roles for heme in protein sorting, and suggest that BACH1 transduces metabolic activity into gene expression.
-
heme positively regulates the expression of β globin at the locus control region via the transcriptional factor BACH1 in erythroid cells
Journal of Biological Chemistry, 2004Co-Authors: Tsuyoshi Tahara, Kazuhiko Igarashi, Jiying Sun, Hiroyoshi Fujita, Katsuyuki Nakanishi, Masafumi Yamamoto, Hajime Mori, Takeshi Saito, Shigeru TaketaniAbstract:Abstract The transcription factor BACH1 heterodimerizes with small Maf proteins to repress Maf recognition element (MARE)-dependent gene expression. The repressor activity of BACH1 is inhibited by the direct binding of heme. To investigate the involvement of BACH1 in the heme-dependent regulation of the expression of the β-globin gene, mouse erythroleukemia (MEL) cells were cultured with succinylacetone (SA), a specific inhibitor of heme biosynthesis, and the level of β-globin mRNA was examined. A marked decrease of β-globin mRNA in SA-treated cells was observed, and this decrease was reversed by the addition of hemin. An iron chelator, desferrioxamine, also lowered the level of β-globin mRNA. The heme-dependent expression of β-globin is a transcriptional event since the expression of the human β-globin gene promoter-reporter gene containing the microlocus control region (μLCR) was inhibited when human erythroleukemia K562 cells and MEL cells were cultured with SA. Hemin treatment restored the decrease in promoter activity caused by SA. The control of the μLCR-β-globin promoter reporter gene by heme was dependent on DNase I-hypersensitive site 2 (HS2), which contains MARE. The MARE binding activity of BACH1 in K562 and MEL cells increased upon SA treatment, and the increase was diminished by the treatment with hemin. Transient expression of BACH1 suppressed the μLCR activity, and this repressor activity was cancelled by treatment with hemin. The expression of a mutated BACH1 lacking heme-binding sites led to a loss in the heme responsiveness of the μLCR. Furthermore, chromatin immunoprecipitation experiments revealed that BACH1 bound to the MARE of HS2 increased by the treatment of MEL cells with SA, and this was cancelled by hemin. We propose that heme positively regulates the β-globin gene expression by blocking the interaction of BACH1 with the MARE in the LCR.
Andrey Brydun - One of the best experts on this subject based on the ideXlab platform.
-
BACH1 Promotes Pancreatic Cancer Metastasis by Repressing Epithelial Genes and Enhancing Epithelial-Mesenchymal Transition.
Cancer Research, 2020Co-Authors: Masaki Sato, Mitsuyo Matsumoto, Andrey Brydun, Hironari Nishizawa, Yuriko Saiki, Mahabub Alam, Masahiro Rokugo, Shinji Yamada, Mika K. Kaneko, Ryo FunayamaAbstract:Pancreatic ductal adenocarcinoma (PDAC) is among the cancers with the poorest prognoses due to its highly malignant features. BTB and CNC homology 1 (BACH1) has been implicated in RAS-driven tumor formation. We focused on the role of BACH1 in PDAC, more than 90% of which have KRAS mutation. Knockdown of BACH1 in PDAC cell lines reduced cell migration and invasion, in part, by increasing E-cadherin expression, whereas its overexpression showed opposite effects. BACH1 directly repressed the expression of FOXA1 that is known to activate the expression of CDH1 encoding E-cadherin and to inhibit epithelial-to-mesenchymal transition. BACH1 also directly repressed the expression of genes important for epithelial cell adhesion including CLDN3 and CLDN4. In a mouse orthotopic implantation model, BACH1 was required for the high metastatic ability of AsPC-1 cells. IHC analysis of clinical specimens with a newly developed anti-BACH1 mAb revealed that high expression of BACH1 is a poor prognostic factor. These results suggest that the gene regulatory network of BACH1 and downstream genes including CDH1 contribute to the malignant features of PDAC by regulating epithelial-to-mesenchymal transition. SIGNIFICANCE: Greater understanding of the gene regulatory network involved in epithelial-to-mesenchymal transition of pancreatic cancer cells will provide novel therapeutic targets and diagnostic markers.
-
Phosphorylation of BACH1 switches its function from transcription factor to mitotic chromosome regulator and promotes its interaction with HMMR.
Biochemical Journal, 2018Co-Authors: Hiroki Shima, Hiroki Kato, Mitsuyo Matsumoto, Masatoshi Ikeda, Andrey Brydun, Hironari Nishizawa, Yuriko Saiki, Liang Liu, Miki Watanabe-matsuiAbstract:The transcription repressor BACH1 performs mutually independent dual roles in transcription regulation and chromosome alignment during mitosis by supporting polar ejection force of mitotic spindle. We now found that the mitotic spindles became oblique relative to the adhesion surface following endogenous BACH1 depletion in HeLa cells. This spindle orientation rearrangement was rescued by re-expression of BACH1 depending on its interactions with HMMR and CRM1, both of which are required for the positioning of mitotic spindle, but independently of its DNA-binding activity. A mass spectrometry analysis of BACH1 complexes in interphase and M phase revealed that BACH1 lost during mitosis interactions with proteins involved in chromatin and gene expression but retained interactions with HMMR and its known partners including CHICA. By analyzing BACH1 modification using stable isotope labeling with amino acids in cell culture, mitosis-specific phosphorylations of BACH1 were observed, and mutations of these residues abolished the activity of BACH1 to restore mitotic spindle orientation in knockdown cells and to interact with HMMR. Detailed histological analysis of BACH1-deficient mice revealed lengthening of the epithelial fold structures of the intestine. These observations suggest that BACH1 performs stabilization of mitotic spindle orientation together with HMMR and CRM1 in mitosis, and that the cell cycle-specific phosphorylation switches the transcriptional and mitotic functions of BACH1.
-
Genomewide approaches for BACH1 target genes in mouse embryonic fibroblasts showed BACH1-Pparg pathway in adipogenesis
Genes to Cells, 2016Co-Authors: Mitsuyo Matsumoto, Ryo Funayama, Keiko Nakayama, Takuma Shiraki, Andrey Brydun, Keiichi Kondo, Nobuo Yaegashi, Hideki Katagiri, Kazuhiko IgarashiAbstract:The transcription repressor BTB and CNC homology 1 (BACH1) represses genes involved in heme metabolism and oxidative stress response. BACH1 also suppresses the p53-dependent cellar senescence in primary mouse embryonic fibroblasts (MEFs). To investigate the role of BACH1 in MEF other than its known functions, we carried out a genomewide mapping of binding site for BACH1 and its heterodimer partner MAFK in immortalized MEFs (iMEFs) using chromatin immunoprecipitation and next-generation sequencing technology (ChIP-sequence). The comparative analysis of the ChIP-sequence data and DNA microarray data from BACH1-deficient and wild-type (WT) iMEF showed 35 novel candidate target genes of BACH1. Among these genes, five genes (Pparg, Nfia, Ptplad2, Adcy1 and Ror1) were related with lipid metabolism. BACH1-deficient iMEFs showed increased expression of mRNA and protein of PPARγ, which is the key factor of adipogenesis. These cells also showed a concomitant increase in ligand-dependent activation of PPARγ target genes compared with wild-type iMEFs. Moreover, BACH1-deficient iMEFs efficiently differentiated to adipocyte compared with wild-type cells in the presence of PPARγ ligands. Our results suggest that BACH1 regulates expression of adipocyte-related genes including Pparg and potentiates adipocyte differentiation capacity.
-
BACH1 Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice
Oxidative Medicine and Cellular Longevity, 2014Co-Authors: Kazushige Ota, Andrey Brydun, Jiying Sun, Ari Itoh-nakadai, Kazuhiko IgarashiAbstract:Oxidative stress contributes to both aging and tumorigenesis. The transcription factor BACH1, a regulator of oxidative stress response, augments oxidative stress by repressing the expression of heme oxygenase-1 (HO-1) gene (Hmox1) and suppresses oxidative stress-induced cellular senescence by restricting the p53 transcriptional activity. Here we investigated the lifelong effects of BACH1 deficiency on mice. BACH1-deficient mice showed longevity similar to wild-type mice. Although HO-1 was upregulated in the cells of BACH1-deficient animals, the levels of ROS in BACH1-deficient HSCs were comparable to those in wild-type cells. BACH1−/−; p53−/− mice succumbed to spontaneous cancers as frequently as p53-deficient mice. BACH1 deficiency significantly altered transcriptome in the liver of the young mice, which surprisingly became similar to that of wild-type mice during the course of aging. The transcriptome adaptation to BACH1 deficiency may reflect how oxidative stress response is tuned upon genetic and environmental perturbations. We concluded that BACH1 deficiency and accompanying overexpression of HO-1 did not influence aging or p53 deficiency-driven tumorigenesis. Our results suggest that it is useful to target BACH1 for acute injury responses without inducing any apparent deteriorative effect.
-
BACH1 is critical for the transformation of mouse embryonic fibroblasts by Ras(V12) and maintains ERK signaling.
Oncogene, 2012Co-Authors: Ayako Nakanome, Mitsuyo Matsumoto, Ryo Funayama, Keiko Nakayama, Andrey Brydun, Kazushige Ota, K Shiga, T Kobayashi, Masao Ono, Kazuhiko IgarashiAbstract:Reactive oxygen species (ROS), by-products of aerobic respiration, promote genetic instability and contribute to the malignant transformation of cells. Among the genes related to ROS metabolism, BACH1 is a repressor of the oxidative stress response, and a negative regulator of ROS-induced cellular senescence directed by p53 in higher eukaryotes. While ROS are intimately involved in carcinogenesis, it is not clear whether BACH1 is involved in this process. We found that senescent BACH1-deficient mouse embryonic fibroblasts (MEFs) underwent spontaneous immortalization the same as did the wild-type cells. When transduced with constitutively active Ras (H-Ras(V12)), the proliferation and colony formation of these cells in vitro were markedly reduced. When transplanted into athymic nude mice, the growth and vascularization of tumors derived from BACH1-deficient cells were also decreased. Gene expression profiling of the MEFs revealed a new H-Ras(V12) signature, which was distinct from the previously reported signatures in epithelial tumors, and was partly dependent on BACH1. The BACH1-deficient cells showed diminished phosphorylation of MEK and ERK1/2 in response to H-Ras(V12), which was consistent with the alterations in the gene expression profile, including phosphatase genes. Finally, BACH1-deficient mice were less susceptible to 4-nitroquinoline-1-oxidide (4-NQO)-induced tongue carcinoma than wild-type mice. Our data provide evidence for a critical role of BACH1 in cell transformation and tumor growth induced by activated H-Ras(V12).
