Orchestration of B lymphoid cells and their inner myeloid by Bach

Igarashi, Kazuhiko; Itoh-Nakadai, Ari

doi:10.1016/j.coi.2016.01.012

Cited by 16 publications

(10 citation statements)

References 38 publications

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“…In each case the genome-wide transcription patterns of the B cells and derived PCs are significantly different, indicating that there is substantial reprogramming of gene expression networks as differentiation proceeds [ 28 ]. This is a very complex process involving many factors, but there is an emerging consensus of opinion that at least 3 transcriptional regulators are essential for differentiation to occur efficiently (reviewed in [ 28 , 30 – 32 ]). These factors are B lymphocyte-induced maturation protein-1 (BLIMP-1), interferon-regulatory factor 4 (IRF4), and a specifically spliced form of X-box binding protein-1 (XBP-1).…”

Section: Introductionmentioning

confidence: 99%

EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency

et al. 2017

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Mature human B cells infected by Epstein-Barr virus (EBV) become activated, grow, and proliferate. If the cells are infected ex vivo, they are transformed into continuously proliferating lymphoblastoid cell lines (LCLs) that carry EBV DNA as extra-chromosomal episomes, express 9 latency-associated EBV proteins, and phenotypically resemble antigen-activated B-blasts. In vivo similar B-blasts can differentiate to become memory B cells (MBC), in which EBV persistence is established. Three related latency-associated viral proteins EBNA3A, EBNA3B, and EBNA3C are transcription factors that regulate a multitude of cellular genes. EBNA3B is not necessary to establish LCLs, but EBNA3A and EBNA3C are required to sustain proliferation, in part, by repressing the expression of tumour suppressor genes. Here we show, using EBV-recombinants in which both EBNA3A and EBNA3C can be conditionally inactivated or using virus completely lacking the EBNA3 gene locus, that—after a phase of rapid proliferation—infected primary B cells express elevated levels of factors associated with plasma cell (PC) differentiation. These include the cyclin-dependent kinase inhibitor (CDKI) p18INK4c, the master transcriptional regulator of PC differentiation B lymphocyte-induced maturation protein-1 (BLIMP-1), and the cell surface antigens CD38 and CD138/Syndecan-1. Chromatin immunoprecipitation sequencing (ChIP-seq) and chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) indicate that in LCLs inhibition of CDKN2C (p18INK4c) and PRDM1 (BLIMP-1) transcription results from direct binding of EBNA3A and EBNA3C to regulatory elements at these loci, producing stable reprogramming. Consistent with the binding of EBNA3A and/or EBNA3C leading to irreversible epigenetic changes, cells become committed to a B-blast fate <12 days post-infection and are unable to de-repress p18INK4c or BLIMP-1—in either newly infected cells or conditional LCLs—by inactivating EBNA3A and EBNA3C. In vitro, about 20 days after infection with EBV lacking functional EBNA3A and EBNA3C, cells develop a PC-like phenotype. Together, these data suggest that EBNA3A and EBNA3C have evolved to prevent differentiation to PCs after infection by EBV, thus favouring long-term latency in MBC and asymptomatic persistence.

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Section: Introductionmentioning

confidence: 99%

EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency

et al. 2017

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“…A recent report by Itoh-Nakadai et al . 17 demonstrated that Bach2 promotes B cell development via the repression of the myeloid program 18 . Bach2 also participates in T-cell-mediated immune responses and regulates T reg -mediated immune homeostasis, and Bach2 null animals suffer from lethal lung and small intestinal inflammation 19 20 .…”

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confidence: 99%

Bach2–Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop

et al. 2016

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Although Bach2 has an important role in regulating the Th2-type immune response, the underlying molecular mechanisms remain unclear. We herein demonstrate that Bach2 associates with Batf and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2–Batf complex antagonizes the recruitment of the Batf–Irf4 complex to AP-1 motifs and suppresses Th2 cytokine production. Furthermore, we find that Bach2 regulates the Batf and Batf3 expressions via two distinct pathways. First, Bach2 suppresses the maintenance of the Batf and Batf3 expression through the inhibition of IL-4 production. Second, the Bach2–Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf–Irf4 complex. These findings suggest that IL-4 and Batf form a positive feedback amplification loop to induce Th2 cell differentiation and the subsequent Th2-type immune response, and Bach2–Batf interactions are required to prevent an excessive Th2 response.

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“…Bach2 promotes lymphoid lineage differentiation by repressing myeloid cell-related genes at the divergence of myeloid and lymphoid progenitors (10,11). After being committed to lymphoid cells, Bach2 plays essential roles for differentiation of both T-and B-lymphoid cells.…”

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confidence: 99%

The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation

Tamahara

Ochiai

Muto

et al. 2017

Molecular and Cellular Biology

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The transcription factor Bach2 regulates both acquired and innate immunity at multiple steps, including antibody class switching and regulatory T cell development in activated B and T cells, respectively. However, little is known about the molecular mechanisms of Bach2 regulation in response to signaling of cytokines and antigen. We show here that mammalian target of rapamycin (mTOR) controls Bach2 along B cell differentiation with two distinct mechanisms in pre-B cells. First, mTOR complex 1 (mTORC1) inhibited accumulation of Bach2 protein in nuclei and reduced its stability. Second, mTOR complex 2 (mTORC2) inhibited FoxO1 to reduce Bach2 mRNA expression. Using expression profiling and chromatin immunoprecipitation assay, the Ccnd3 gene, encoding cyclin D3, was identified as a new direct target of Bach2. A proper cell cycle was lost at pre-B and mature B cell stages in Bach2-deficient mice. Furthermore, AZD8055, an mTOR inhibitor, increased class switch recombination in wild-type mature B cells but not in Bach2-deficient cells. These results suggest that the mTOR-Bach2 cascade regulates proper cell cycle arrest in B cells as well as immunoglobulin gene rearrangement.

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Orchestration of B lymphoid cells and their inner myeloid by Bach

Cited by 16 publications

References 38 publications

EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency

EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency

Bach2–Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop

The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation

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