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1.  The Bright Side of Hematopoiesis: Regulatory Roles of ARID3a/Bright in Human and Mouse Hematopoiesis 
ARID3a/Bright is a DNA-binding protein that was originally discovered for its ability to increase immunoglobulin transcription in antigen-activated B cells. It interacts with DNA as a dimer through its ARID, or A/T-rich interacting domain. In association with other proteins, ARID3a increased transcription of the immunoglobulin heavy chain and led to improved chromatin accessibility of the heavy chain enhancer. Constitutive expression of ARID3a in B lineage cells resulted in autoantibody production, suggesting its regulation is important. Abnormal ARID3a expression has also been associated with increased proliferative capacity and malignancy. Roles for ARID3a in addition to interactions with the immunoglobulin locus were suggested by transgenic and knockout mouse models. Over-expression of ARID3a resulted in skewing of mature B cell subsets and altered gene expression patterns of follicular B cells, whereas loss of function resulted in loss of B1 lineage B cells and defects in hematopoiesis. More recent studies showed that loss of ARID3a in adult somatic cells promoted developmental plasticity, alterations in gene expression patterns, and lineage fate decisions. Together, these data suggest new regulatory roles for ARID3a. The genes influenced by ARID3a are likely to play pivotal roles in lineage decisions, highlighting the importance of this understudied transcription factor.
doi:10.3389/fimmu.2014.00113
PMCID: PMC3958700  PMID: 24678314
Bright; ARID3a; hematopoietic regulation; B cell development; gene regulation
2.  Serum Amyloid A Protects Murine Macrophages from Lethal Toxin-Mediated Death1 
Cellular immunology  2011;272(2):175-181.
Lethal toxin, a key virulence factor produced by Bacillus anthracis, induces cell death, in part by disrupting numerous signaling pathways, in mouse macrophages. However, exposure to sublethal doses of lethal toxin allows some cells to survive. Because these pro-survival signaling events occur within a few hours after exposure to sublethal doses, we hypothesized that acute phase proteins might influence macrophage survival. Our data show that serum amyloid A (SAA) is produced in response to lethal toxin treatment. Moreover, pre-treatment of macrophages with exogenous SAA protected macrophages from lethal toxin-mediated death. Exogenous SAA activated the p38 mitogen activated protein kinase (MAP) kinase pathway, while lethal toxin mutants incapable of p38 activation were incapable of causing cell death. Chemical inhibition of the p38 activation pathway abrogated the protective effects of SAA. These data show that SAA affords protection against lethal toxin in mouse macrophages and link this response to the p38 pathway.
doi:10.1016/j.cellimm.2011.10.014
PMCID: PMC3244522  PMID: 22082566
anthrax lethal toxin; acute phase proteins; serum amyloid A
3.  Bright/Arid3A Acts as a Barrier to Somatic Cell Reprogramming through Direct Regulation of Oct4, Sox2, and Nanog 
Stem Cell Reports  2014;2(1):26-35.
Summary
We show here that singular loss of the Bright/Arid3A transcription factor leads to reprograming of mouse embryonic fibroblasts (MEFs) and enhancement of standard four-factor (4F) reprogramming. Bright-deficient MEFs bypass senescence and, under standard embryonic stem cell (ESC) culture conditions, spontaneously form clones that in vitro express pluripotency markers, differentiate to all germ lineages, and in vivo form teratomas and chimeric mice. We demonstrate that BRIGHT binds directly to the promoter/enhancer regions of Oct4, Sox2, and Nanog to contribute to their repression in both MEFs and ESCs. Thus, elimination of the BRIGHT barrier may provide an approach for somatic cell reprogramming.
Highlights
•Loss of Bright can alone reprogram or enhance conventional four-factor reprogramming•Bright directly represses Oct4, Sox2, and Nanog•Bright may function in somatic and embryonic stem cells to enforce differentiation
Popowski et al. show that loss of the transcription factor Bright/Arid3A induces reprogramming in mouse embryonic fibroblasts (MEFs) and enhancement of standard four-factor reprograming. Bright-deficient reprogrammed cells express all pluripotency markers and are capable of forming teratomas and chimeric mice. Bright binds directly to the promoter/enhancer regions of Oct4, Sox2, and Nanog and contributes to their repression in both MEFs and embryonic stem cells.
doi:10.1016/j.stemcr.2013.12.002
PMCID: PMC3916758  PMID: 24511468
4.  The Transcription Factor Bright Plays a Role in Marginal Zone B Lymphocyte Development and Autoantibody Production 
Molecular immunology  2011;49(1-2):367-379.
Previous data suggested that constitutive expression of the transcription factor Bright (B cell regulator of immunoglobulin heavy chain transcription), normally tightly regulated during B cell differentiation, was associated with autoantibody production. Here we show that constitutive Bright expression results in skewing of mature B lineage subpopulations toward marginal zone cells at the expense of the follicular subpopulation. C57Bl/6 transgenic mice constitutively expressing Bright in B lineage cells generated autoantibodies that were not the result of global increases in immunoglobulin or of breaches in key tolerance checkpoints typically defective in other autoimmune mouse models. Rather, autoimmunity correlated with increased numbers of marginal zone B cells and alterations in the phenotype and gene expression profiles of lymphocytes within the follicular B cell compartment. These data suggest a novel role for Bright in the normal development of mature B cell subsets and in autoantibody production.
doi:10.1016/j.molimm.2011.09.008
PMCID: PMC3205293  PMID: 21963220
Bright transcription factor; B lymphocyte; autoantibodies; marginal zone development
5.  Loss of Bright/ARID3a Function Promotes Developmental Plasticity 
Stem cells (Dayton, Ohio)  2010;28(9):1560-1567.
Bright (B cell regulator of immunoglobulin heavy chain transcription)/ARID3a, an A+T-rich interaction domain protein, was originally discovered in B lymphocyte lineage cells. However, expression patterns and high lethality levels in knockout mice suggested it had additional functions. Three independent lines of evidence show that functional inhibition of Bright results in increased developmental plasticity. Bright-deficient cells from two mouse models expressed a number of pluripotency-associated gene products, expanded indefinitely and spontaneously differentiated into cells of multiple lineages. Furthermore, direct knockdown of human Bright resulted in colonies capable of expressing multiple lineage markers. These data suggest that repression of this single molecule confers adult somatic cells with new developmental options.
doi:10.1002/stem.491
PMCID: PMC2977942  PMID: 20680960
ARID3a; multipotency
6.  Transgenic Mice Expressing Dominant Negative Bright Exhibit Defects in B1 B Cells 
The transcription factor Bright up-regulates immunoglobulin heavy chain production from select variable region promoters and requires Bright dimerization, Bruton’s tyrosine kinase (Btk) and the Btk substrate, TFII-I for this activity. Defects in Btk cause X-linked immunodeficiency disease in mice and man. Btk-deficient mice exhibit decreased serum IgM production, B cell developmental blocks, absence of peritoneal B1 cells, and subnormal immune responses against antigens, including phosphorylcholine, which confer protection against Streptococcus pneumoniae. Transgenic mice expressing dominant negative (DN) Bright share similarities with Btk-deficient mice, including decreased serum IgM, poor anti-phosphorylcholine responses, and slightly reduced numbers of mature B cells. Although DN Bright mice developed B1 B cells, these were functionally deficient in immunoglobulin secretion. These data suggest a mechanistic explanation for the abnormal responses to phosphorylcholine observed in Btk-deficient mice, and indicate that Bright functions in a subset of Btk-dependent pathways in vivo, particularly those responses dominated by B1 B cells.
PMCID: PMC2636627  PMID: 18981111
7.  Anti-Nuclear Antibody Production and Autoimmunity in Transgenic Mice that Over-Express the Transcription Factor Bright 
The B cell-restricted transcription factor, Bright, up-regulates immunoglobulin heavy chain transcription three- to seven-fold in activated B cells in vitro. Bright function is dependent upon both active Bruton’s tyrosine kinase and its substrate, the transcription factor, TFII-I. In mouse and human B lymphocytes, Bright transcription is down regulated in mature B cells, and its expression is tightly regulated during B cell differentiation. To determine how Bright expression affects B cell development, transgenic mice were generated that express Bright constitutively in all B lineage cells. These mice exhibited increases in total B220+ B lymphocyte lineage cells in the bone marrow, but the relative percentages of the individual subpopulations were not altered. Splenic immature transitional B cells were significantly expanded both in total cell numbers and as increased percentages of cells relative to other B cell subpopulations. Serum immunoglobulin levels, particularly IgG isotypes, were increased slightly in the Bright transgenic mice compared to littermate controls. However, immunization studies suggest that responses to all foreign antigens were not increased globally. Moreover, four week-old Bright transgenic mice produced anti-nuclear antibodies. Older animals developed antibody deposits in the kidney glomeruli, but did not succumb to further autoimmune sequelae. These data indicate that enhanced Bright expression results in failure to maintain B cell tolerance and suggest a previously unappreciated role for Bright regulation in immature B cells. Bright is the first B cell-restricted transcription factor demonstrated to induce autoimmunity. Therefore, the Bright transgenics provide a novel model system for future analyses of B cell autoreactivity.
PMCID: PMC2705967  PMID: 17312145
autoimmunity; Bright; B cell
8.  The Transcription Factor Encyclopedia 
Yusuf, Dimas | Butland, Stefanie L | Swanson, Magdalena I | Bolotin, Eugene | Ticoll, Amy | Cheung, Warren A | Cindy Zhang, Xiao Yu | Dickman, Christopher TD | Fulton, Debra L | Lim, Jonathan S | Schnabl, Jake M | Ramos, Oscar HP | Vasseur-Cognet, Mireille | de Leeuw, Charles N | Simpson, Elizabeth M | Ryffel, Gerhart U | Lam, Eric W-F | Kist, Ralf | Wilson, Miranda SC | Marco-Ferreres, Raquel | Brosens, Jan J | Beccari, Leonardo L | Bovolenta, Paola | Benayoun, Bérénice A | Monteiro, Lara J | Schwenen, Helma DC | Grontved, Lars | Wederell, Elizabeth | Mandrup, Susanne | Veitia, Reiner A | Chakravarthy, Harini | Hoodless, Pamela A | Mancarelli, M Michela | Torbett, Bruce E | Banham, Alison H | Reddy, Sekhar P | Cullum, Rebecca L | Liedtke, Michaela | Tschan, Mario P | Vaz, Michelle | Rizzino, Angie | Zannini, Mariastella | Frietze, Seth | Farnham, Peggy J | Eijkelenboom, Astrid | Brown, Philip J | Laperrière, David | Leprince, Dominique | de Cristofaro, Tiziana | Prince, Kelly L | Putker, Marrit | del Peso, Luis | Camenisch, Gieri | Wenger, Roland H | Mikula, Michal | Rozendaal, Marieke | Mader, Sylvie | Ostrowski, Jerzy | Rhodes, Simon J | Van Rechem, Capucine | Boulay, Gaylor | Olechnowicz, Sam WZ | Breslin, Mary B | Lan, Michael S | Nanan, Kyster K | Wegner, Michael | Hou, Juan | Mullen, Rachel D | Colvin, Stephanie C | Noy, Peter John | Webb, Carol F | Witek, Matthew E | Ferrell, Scott | Daniel, Juliet M | Park, Jason | Waldman, Scott A | Peet, Daniel J | Taggart, Michael | Jayaraman, Padma-Sheela | Karrich, Julien J | Blom, Bianca | Vesuna, Farhad | O'Geen, Henriette | Sun, Yunfu | Gronostajski, Richard M | Woodcroft, Mark W | Hough, Margaret R | Chen, Edwin | Europe-Finner, G Nicholas | Karolczak-Bayatti, Magdalena | Bailey, Jarrod | Hankinson, Oliver | Raman, Venu | LeBrun, David P | Biswal, Shyam | Harvey, Christopher J | DeBruyne, Jason P | Hogenesch, John B | Hevner, Robert F | Héligon, Christophe | Luo, Xin M | Blank, Marissa Cathleen | Millen, Kathleen Joyce | Sharlin, David S | Forrest, Douglas | Dahlman-Wright, Karin | Zhao, Chunyan | Mishima, Yuriko | Sinha, Satrajit | Chakrabarti, Rumela | Portales-Casamar, Elodie | Sladek, Frances M | Bradley, Philip H | Wasserman, Wyeth W
Genome Biology  2012;13(3):R24.
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.
doi:10.1186/gb-2012-13-3-r24
PMCID: PMC3439975  PMID: 22458515
9.  The ARID Family Transcription Factor Bright Is Required for both Hematopoietic Stem Cell and B Lineage Development▿  
Molecular and Cellular Biology  2011;31(5):1041-1053.
Bright/Arid3a has been characterized both as an activator of immunoglobulin heavy-chain transcription and as a proto-oncogene. Although Bright expression is highly B lineage stage restricted in adult mice, its expression in the earliest identifiable hematopoietic stem cell (HSC) population suggests that Bright might have additional functions. We showed that >99% of Bright−/− embryos die at midgestation from failed hematopoiesis. Bright−/− embryonic day 12.5 (E12.5) fetal livers showed an increase in the expression of immature markers. Colony-forming assays indicated that the hematopoietic potential of Bright−/− mice is markedly reduced. Rare survivors of lethality, which were not compensated by the closely related paralogue Bright-derived protein (Bdp)/Arid3b, suffered HSC deficits in their bone marrow as well as B lineage-intrinsic developmental and functional deficiencies in their peripheries. These include a reduction in a natural antibody, B-1 responses to phosphocholine, and selective T-dependent impairment of IgG1 class switching. Our results place Bright/Arid3a on a select list of transcriptional regulators required to program both HSC and lineage-specific differentiation.
doi:10.1128/MCB.01448-10
PMCID: PMC3067827  PMID: 21199920
10.  Association Between a Functional Variant Downstream of TNFAIP3 and Systemic Lupus Erythematosus 
Nature genetics  2011;43(3):253-258.
Systemic Lupus Erythematosus (SLE, OMIM 152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic resequencing in ethnically diverse populations we fully characterized the TNFAIP3 risk haplotype and isolated a novel TT>A polymorphic dinucleotide associated with SLE in subjects of European (P = 1.58 × 10−8; odds ratio (OR) = 1.70) and Korean (P = 8.33 × 10−10; OR = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex comprised of NF-κB subunits with reduced avidity. Furthermore, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.
doi:10.1038/ng.766
PMCID: PMC3103780  PMID: 21336280
11.  Retinoids Accelerate B Lineage Lymphoid Differentiation 
Retinoids are known to have potent effects on hematopoietic stem cell integrity, and our objective was to learn if they influence cells destined to replenish the immune system. Total CD19+ B lineage cells increased substantially in marrow and spleens of ATRA treated C57BL6 mice, while lymphoid progenitors were reduced. All B lymphoid progenitors were targets of ATRA in culture and overall cell yields declined without reductions in proliferation. Remarkably, ATRA shortened the time required for primitive progenitors to generate CD19+ cells. PCR analysis and a panel of RAR/RXR agonist treatments suggested that RARα mediates these responses. The transcription factors EBF1 and Pax-5 were elevated during treatment and ATRA had similar effects on human B cell differentiation. That is, it inhibited the expansion of human progenitor cells and accelerated their differentiation to B lineage cells. There may be previously unsuspected side effects of ATRA therapy, and the new findings suggest retinoids can normally contribute to the lymphopoietic environment in bone marrow.
PMCID: PMC2597070  PMID: 18097013
12.  Induction of Immunoglobulin Heavy-Chain Transcription through the Transcription Factor Bright Requires TFII-I 
Molecular and Cellular Biology  2006;26(12):4758-4768.
Bright/ARID3a/Dril1, a member of the ARID family of transcription factors, is expressed in a highly regulated fashion in B lymphocytes, where it enhances immunoglobulin transcription three- to sixfold. Recent publications from our lab indicated that functional, but not kinase-inactive, Bruton's tyrosine kinase (Btk) is critical for Bright activity in an in vitro model system, yet Bright itself is not appreciably tyrosine phosphorylated. These data suggested that a third protein, and Btk substrate, must contribute to Bright-enhanced immunoglobulin transcription. The ubiquitously expressed transcription factor TFII-I was identified as a substrate for Btk several years ago. In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels. These data suggest that Bright functions as a three-component protein complex in the immunoglobulin locus and tie together previous data indicating important roles for Btk and TFII-I in B lymphocytes.
doi:10.1128/MCB.02009-05
PMCID: PMC1489113  PMID: 16738337
13.  Bruton's Tyrosine Kinase Regulates Immunoglobulin Promoter Activation in Association with the Transcription Factor Bright 
Molecular and Cellular Biology  2005;25(6):2073-2084.
Bright (B-cell regulator of immunoglobulin heavy chain transcription) binding to immunoglobulin heavy chain loci after B-cell activation is associated with increased heavy chain transcription. Our earlier reports demonstrated that Bright coimmunoprecipitates with Bruton's tyrosine kinase (Btk) and that these proteins associate in a DNA-binding complex in primary B cells. B cells from immunodeficient mice with a mutation in Btk failed to produce stable Bright DNA-binding complexes. In order to determine if Btk is important for Bright function, a transcription activation assay was established and analyzed using real-time PCR technology. Cells lacking both Bright and Btk were transfected with Bright and/or Btk along with an immunoglobulin heavy chain reporter construct. Immunoglobulin gene transcription was enhanced when Bright and Btk were coexpressed. In contrast, neither Bright nor Btk alone led to activation of heavy chain transcription. Furthermore, Bright function required both Btk kinase activity and sequences within the pleckstrin homology domain of Btk. Bright was not appreciably phosphorylated by Btk; however, a third tyrosine-phosphorylated protein coprecipitated with Bright. Thus, the ability of Bright to enhance immunoglobulin transcription critically requires functional Btk.
doi:10.1128/MCB.25.6.2073-2084.2005
PMCID: PMC1061591  PMID: 15743806

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