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The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program

ABSTRACT: Mature lymphoid cells express the transcriptional 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. Bach2hi 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE61409 | GEO | 2014/10/26

SECONDARY ACCESSION(S): PRJNA261019

REPOSITORIES: GEO

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The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program

Project description:Mature lymphoid cells express the transcriptional 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 (M-bM-^@M-^Xmyeloid genesM-bM-^@M-^Y). Bach2 and Bach1 bound to presumptive regulatory regions of the myeloid genes. Bach2hi 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. WT and Bach1 and Bach2 double deficient (DD) CLPs. Multipotent progenitors (MPPs) infected with control-GFP and Bach2-GFP and cultured several condition. Follicular B cells (Fo B) stimulated with IgM. Three expreriments was performed in this paper.

2014-10-26 | E-GEOD-61409 | biostudies-arrayexpress

Double knockout of Bach1 and Bach2 reveals shared compensatory mechanisms in regulating alveolar macrophage function and lung surfactant homeostasis [ChIP-Seq]

Project description:Background: Pulmonary alveolar proteinosis (PAP) is a rare disease showing excess accumulation of surfactant protein in the alveolar spaces. It chiefly results from a dysfunction of alveolar macrophages (AMs) due to a lack of granulocyte macrophage colony-stimulating factor (GM-CSF) signaling including the expression of PU.1. We previously reported that mice deficient for Bach2 developed PAP-like disease due to a defect of lipid handling by AMs. Recently, Bach1 and Bach2 have been reported to function redundantly in early B cell development. The aim of this study was to investigate the function of Bach1 and Bach2 in alveolar macrophage and lung homeostasis. Methods: We generated mice lacking both Bach1 and Bach2 (Bach1/2 DKO mice) and investigated their body weight and survival rate. Whole lungs of mice were observed with Hematoxylin and eosin (HE) stain when they were 8 or 12-13 weeks old. The expression of surface markers and the numbers of alveolar macrophages and eosinophils in BAL were analyzed by flow cytometry (FACS). We also analyzed tissue macrophages in bone marrow and spleen by FACS. We administered N-acetyl cysteine to mice from prenatal stage and observed lung pathology at 12 weeks. Result: Bach1/2 DKO mice showed a more rapid and severe PAP phenotype than Bach2-deficient mice (Bach2 KO mice), whereas Bach1-deficient mice (Bach1 KO mice) did not develop any pulmonary disease. AMs in Bach1/2 DKO mice showed a foamy appearance, suggesting a defect in lipid handling. In contrast, the numbers of bone marrow macrophages and red pulp macrophages were not affected in Bach1/2 DKO mice. The PAP-like disease in Bach1/2 DKO and Bach2 KO mice was not ameliorated by N-acetyl cysteine. Conclusion: We suggest that Bach1 and Bach2 work in a complementary manner for the normal function of AMs and the maintenance of surfactant homeostasis in the lungs. Oxidative stress may be involved in the process of PAP by inactivating Bach1 and Bach2.

2018-11-05 | GSE79138 | GEO

A Bach2-Cebp gene regulatory network for the commitment of multipotent hematopoietic progenitors [ChIP-seq]

Project description:The commitment of hematopoietic stem cells and multipotent progenitors (MPPs) can be tuned to reprogram their differentiation capacity to be biased toward myeloid cells in response to an infection. Bach2, which inhibits myeloid differentiation in common lymphoid progenitors, repressed a cohort of genes of myeloid function (myeloid genes) and activated those for lymphoid function (lymphoid genes) in MPPs. In addition, Bach2 repressed both Cebpb and its target Csf1, encoding C/EBPβ and macrophage colony-stimulating factor (M-CSF), respectively, whereas C/EBPβ repressed Bach2 and activated the M-CSF receptor gene Csf1r. Bach2 and C/EBPβ bound to overlapping regulatory regions of their myeloid target genes, suggesting the presence of a gene regulatory network (GRN) with mutual repression and antagonistic, feed-forward regulation of myeloid genes. Lipopolysaccharide reduced the expression of Bach2, resulting in enhanced myeloid differentiation. Bach2 tunes the commitment of multipotent progenitors to myeloid and lymphoid lineages under both normal and infectious conditions.

2017-03-13 | GSE87503 | GEO

A Bach2-Cebp gene regulatory network for the commitment of multipotent hematopoietic progenitors [expression]

Project description:Hematopoietic stem cells and multipotent progenitors (MPPs) commitment can be tuned in response to an infection so that their differentiation is biased toward myeloid cells. Here we find that Bach2, which inhibits myeloid differentiation in common lymphoid progenitors, represses a cohort of myeloid genes and activates those linked to lymphoid function. Bach2 repressed both Cebpb and its target Csf1r, encoding C/EBPβ and macrophage colony-stimulating factor receptor (M-CSFr), respectively, whereas C/EBPβ repressed Bach2 and activated Csf1r. Bach2 and C/EBPβ further bound to overlapping regulatory regions at their myeloid target genes, suggesting the presence of a gene regulatory network (GRN) with mutual repression and antagonistic, feed-forward myeloid gene regulations. Lipopolysaccharide reduced the expression of Bach2, resulting in enhanced myeloid differentiation. The Bach2-C/EBPβ GRN pathway thus tunes MPP commitment to myeloid and lymphoid lineages under both normal conditions and after infection.

2017-03-07 | GSE80954 | GEO

Expression profiling of early lymphoid progenitors deficient for Ebf1 and Foxo1

Project description:Foxo1 and Ebf1 deficiency leads to a similar disruption of normal B-cell development at the level of the common lymphoid progenitor (CLP). Both mouse strains display the existance of LY6D+ CLPs but a marked/complete lack of proB cells. To investigate similarities of the developmental defects observed we generated gene expression profiles from both genotypes (with corresponding WT controls). This illustrated a shared gene expression signature in Ebf1/Foxo1 deficient CLPs. Gene expression profiling was done using highly purified (FACS sorted) progenitor cells. Cells were purified from bone marrow of wild-type, Foxo1 deficient and Ebf1 deficient mice. Ebf1 deficient bone marrow was aquired by transplantation of Ebf1 deficient progenitors into irradiated hosts. Populations analysed were CLP LY6D-, CLP LY6D+ and proB cells.

2012-11-01 | E-GEOD-41931 | biostudies-arrayexpress

Expression profiling of early lymphoid progenitors deficient for Ebf1 and Foxo1

2012-11-01 | GSE41931 | GEO

Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function.

Project description:Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling. WT (n=8) and Bach2KO (n=3) AMs. One expreriment was performed.

2014-01-15 | E-GEOD-54050 | biostudies-arrayexpress

Super-killer CTLs are generated by single gene deletion of Bach2

Project description:Bach2 codes for a transcriptional regulator exerting major influences on T cell mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.

2022-09-02 | PXD036457 | Pride

Genome-wide map of BACH1 binding in HEK 293T cells

Project description:BTB and CNC homology 1 (BACH1) is a heme-binding transcription factor repressing the transcription from a subset of MAF recognition elements (MAREs) at low intracellular heme levels. Upon heme binding, BACH1 is released from the MAREs, resulting in increased expression of antioxidant response genes. To systematically address the gene regulatory networks involving BACH1, we combined chromatin immunoprecipitation-sequencing (ChIP-seq) analysis of BACH1 target genes in HEK 293 cells with knock-down of BACH1 using three independent types of small interfering RNAs followed by transcriptome profiling using microarrays. The 59 BACH1 target genes identified by ChIP-seq were found highly enriched in genes showing expression changes after BACH1 knock-down, demonstrating the impact of BACH1 repression on transcription. In addition to known and new BACH1 targets involved in heme degradation (HMOX1, FTL, FTH1, ME1, SLC48A1) and redox regulation (GCLC, GCLM, SLC7A11), we also discovered BACH1 target genes effecting cell cycle and apoptosis pathways (ITPR2, CALM1, SQSTM1, TFE3, EWSR1, CDK6, BCL2L11, MAFG) as well as subcellular transport processes (CLSTN1, PSAP, MAPT, vault RNA). The newly identified impact of BACH1 on genes involved in neurodegenerative processes and proliferation provides an interesting basis for future dissection of BACH1-mediated gene repression in neurodegeneration and virus-induced cancerogenesis. Examination of BACH1 binding in HEK 293T cells by chromatin immunoprecipitation-sequencing (CHIP-seq) with input DNA as control.

2011-05-13 | E-GEOD-28051 | biostudies-arrayexpress

EBF1 contributes to the balance of lympho-myeloid fate in haematopoietic progenitors via B-lymphoid priming and Cebpa antagonism [ATAC-seq]

Project description:Haematopoietic stem cells (HSC) and multipotent progenitor cells (MPP) generate all cells of the blood system, although cellular heterogeneity and bias in lineage potential have been observed. Here, we examined whether lineage-specific transcription factors, such as the B-lineage determinant EBF1, establish lineage bias in early progenitors. We detect low level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, and show that Ebf1-deficient animals display reduced HSC quiescence and repopulation capacity, enhanced myelopoiesis and enhanced myeloid differentiation potential of MPP3 and MPP4 cells. Bulk and single-cell RNA-seq analysis revealed a CEBPa-driven myeloid transcriptome in Ebf1-deficient progenitors, and we find that EBF1 binds and potentially antagonizes the haematopoietic Cebpa enhancer. In MPP3 cells, EBF1 additionally primes enhancers associated with B-lymphoid genes that gain expression in common lymphoid progenitors. Thus, our study identifies EBF1 as an important determinant in regulating the balance of myeloid versus lymphoid potential in the earliest hematopoietic progenitors.

2022-06-30 | GSE189049 | GEO

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