Human BSAP and BLIMP1 conform an autoregulatory feedback loop

Mora-López, Francisco; Reales, Elena; Brieva, José A.; Campos‐Caro, Antonio

doi:10.1182/blood-2007-05-092262

Cited by 32 publications

(33 citation statements)

References 51 publications

(85 reference statements)

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“…2). Given that Pax5 has been suggested to directly repress PRDM1 [39], we investigated whether Pax5 is responsible for the repression of PRDM1. Pax5 expression in BCL6 À/À cells was not able to downregulate PRDM1, showing that Pax5 is not sufficient to repress PRDM1 expression in the absence of Bcl6 ( Fig.…”

Section: Inactivation Of Bcl6 In B Cells Induces Plasma Cell Differenmentioning

confidence: 99%

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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The transcription factor Bcl6 regulates germinal center formation and differentiation of B cells into high-affinity antibody-producing plasma cells. The direct double-negative regulatory circuit between Bcl6 and Blimp-1 is well established. We now reveal alternative mechanisms for Bcl6-mediated regulation of B-cell differentiation to plasma cells and show with DT40 cells that Bcl6 directly promotes the expression of Bach2, a known suppressor of Blimp-1. Moreover, Bcl6 suppresses Blimp-1 expression through direct binding to the IRF4 gene, as well as by promoting the expression of MITF, a known suppressor of IRF4. We also provide evidence that Bcl6 is needed for the expression of AID and UNG, the indispensable proteins for somatic hypermutation and class-switch recombination, and UNG appears to be a direct Bcl6 target. Our findings reveal a complex regulatory network in which Bcl6 acts as a key element dictating the transition of DT40 B cells to plasma cells. Supporting Information available online See accompanying Commentary by Tarlinton IntroductionThe transition of activated B cells into high-affinity antibodyproducing plasmablasts, plasma cells and memory B cells in the germinal centers (GCs) is a biologically unique process involving rapid B-cell proliferation coupled with a high rate of mutation in the variable regions of immunoglobulin (Ig) genes. Considering that the majority of B-cell lymphomas originate from the GC B cells [1], a comprehensive understanding of the transcriptional regulation controlling the transition of B cells to plasma cells is essential. The transcription factors Blimp-1, Xbp-1 and IRF4 have been identified to be critical regulators promoting the Ig secretion and plasma cell phenotype, whereas Pax5, Bcl6, MITF and Bach2 are the known inhibitors of plasma cell development [2].Previous studies have shown that the downregulation of B-cell identity factor Pax5 occurs before the induction of the plasma cell transcription program [3,4], and that the loss of Pax5 expression [4] leads to the downregulation of BCL6. Furthermore, B-cell receptor (BCR) signaling of sufficient affinity leads to rapid phosphorylation and degradation of Bcl6 protein [5], while Bcl6 can also be functionally inactivated by acetylation [6]. These features of Bcl6 make it a prominent molecular trigger that controls the plasma cell differentiation.The transcription factor Bcl6 has been demonstrated to be essential for GC B-cell development, as Bcl6 knockout mice fail to develop GCs and do not produce high-affinity antibodies [7][8][9]. Recent work revealed that Bcl6 is also needed for follicular T helper cell development [10][11][12]. Analyses of Bcl6 target genes in B cells indicate that suppression of apoptosis and cell cycle arrest responses occur through p53, p21 and CHEK1 and Bcl6 also regulates DNA damage responses by controlling ATR [13][14][15][16]. Thus, Bcl6 appears to function as a factor permitting rapid B-cell 2404proliferation and tolerance for DNA damage in GCs. Bcl6 also represses genes that are involve...

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Section: Inactivation Of Bcl6 In B Cells Induces Plasma Cell Differenmentioning

confidence: 99%

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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Section: Identification Of Dna Sequences Required For Prdm1 Transcripmentioning

confidence: 99%

“…DNA-protein binding assays, competitions and supershift assays were performed as described [20]. All antibodies used were obtained from Santa Cruz Biotechnology (Santa Cruz, CA): anti-SP1 (sc-17824X), anti-SP3 (sc-644X) and anti-EGR-1 (sc-110X).…”

Section: Rpa and Pe Assaysmentioning

confidence: 99%

“…These results mean that -123/+138 region contains the minimal promoter region necessary for PRDM1 transcription. Recently, we have demonstrated a functional binding site for BSAP TF on the exon-1 (+1/+138) [20]; hence we decided to analyze the possible positive regulatory elements located upstream of the exon-1 (-123/+5) necessary for basal transcription of the human PRDM1 gene.Additional positive elements, located upstream of this region, may be operative, as demonstrated by the increased activity of larger constructs, i.e. pGL3-(-2230/+138) compared to pGL3-(-1319/+138), (Supporting Information Fig.…”

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confidence: 99%

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Transcription of PRDM1, the master regulator for plasma cell differentiation, depends on an SP1/SP3/EGR‐1 GC‐box

et al. 2008

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The positive regulatory domain containing 1, encoded by the PRDM1 gene, is a transcriptional repressor considered as a master regulator that is required and sufficient for plasma cell differentiation. In the present study we have performed sequence analysis of the upstream region of the human PRDM1 gene to detect the minimal promoter region necessary for PRDM1 gene transcription. This region comprises the region upstream of the initiation site, as well as the first exon. Collectively, deletion and mutation analysis in conjunction with luciferase reporter assays, EMSA and supershift assays identified a phylogenetically conserved GC-box as an essential element for PRDM1 expression. This GC-box element matches to a binding site for multiple transcription factors such as SP1 and SP3 isoforms as well as early growth response 1. Chromatin immunoprecipitation assays confirmed the in vivo binding capability of these factors to the human PRDM1 promoter. These studies together characterize for the first time the basal activity of the human PRDM1 promoter, through which several factors, including SP1, SP3 and early growth response 1, modulate its expression through a conserved GC-box.Key words: B cell differentiation Á Human Á PRDM1 Á Transcription factors Supporting Information available online IntroductionPlasma cells (PC), i.e. terminally differentiated B lymphocytes in a post-mitotic state, are immunoglobulin (Ig)-secreting cells playing a central role in the antigen-specific immune response. The plasmacytic differentiation process is regulated by the "turn off" and "turn on" of many specific transcription factors (TF), which are now starting to be elucidated [1][2][3][4]. One of these, the human positive regulatory domain containing 1 with zinc-finger domain (PRDM1), is considered as a key factor that promotes the nonproliferative and differentiated stage of PC [4, 5]. The PRDM1 factor was initially identified as a 98-kDa DNA-binding protein that contains five zinc-finger domains and acts as a repressor of interferon-b gene expression [6]. Its murine homolog, initially called B lymphocyte-induced maturation protein-1 (Blimp-1), was isolated as a mouse gene that is induced during B lymphocyte maturation [7]. It is expressed at high levels only in late B cells and PC, and the ectopic overexpression of PRDM1 is sufficient to drive B lymphocytes to differentiate into PC [7]. Moreover, its expression is required for the formation of Ig-secreting cells [8] and for the maintenance of long-lived PC in bone marrow [9].MYC Here we have defined the minimal promoter for human PRDM1 transcription enclosing a GC-rich element necessary for basal transcription. Moreover, this GC-rich element contains an SP1/early growth response 1 (EGR-1) overlapping binding site to which the regulatory factors SP1, SP3 and EGR-1 can bind, which activate the PRDM1 transcription. Results and discussionStructure of the 5 0 -flanking region and initiation sites of the human PRDM1 gene To obtain insight into the regulation of the human PRDM1 gene and b...

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“…However, other models have been proposed in the literature, several of them aiming to address the earlier developmental decision of undergoing CSR and SHM versus progressing to further differentiation. PAX5, a transcription factor required for both the establishment of the B-cell lineage identity and the process of CSR and SHM (23), and BLIMP1 have been shown to mutually repress each other's expression in a doublenegative feedback loop (24). This binary switch has been proposed to produce a delay in BLIMP1 induction necessary to undergo CSR (25).…”

Section: Gc-exit Pathway Modelmentioning

confidence: 99%

Quantitative modeling of the terminal differentiation of B cells and mechanisms of lymphomagenesis

Martínez

Corradin

Klein

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Mature B-cell exit from germinal centers is controlled by a transcriptional regulatory module that integrates antigen and T-cell signals and, ultimately, leads to terminal differentiation into memory B cells or plasma cells. Despite a compact structure, the module dynamics are highly complex because of the presence of several feedback loops and self-regulatory interactions, and understanding its dysregulation, frequently associated with lymphomagenesis, requires robust dynamical modeling techniques. We present a quantitative kinetic model of three key gene regulators, BCL6, IRF4, and BLIMP, and use gene expression profile data from mature human B cells to determine appropriate model parameters. The model predicts the existence of two different hysteresis cycles that direct B cells through an irreversible transition toward a differentiated cellular state. By synthetically perturbing the interactions in this network, we can elucidate known mechanisms of lymphomagenesis and suggest candidate tumorigenic alterations, indicating that the model is a valuable quantitative tool to simulate B-cell exit from the germinal center under a variety of physiological and pathological conditions.

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Human BSAP and BLIMP1 conform an autoregulatory feedback loop

Cited by 32 publications

References 51 publications

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

Transcription of PRDM1, the master regulator for plasma cell differentiation, depends on an SP1/SP3/EGR‐1 GC‐box

Quantitative modeling of the terminal differentiation of B cells and mechanisms of lymphomagenesis

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