Characterization of ABF-1, a Novel Basic Helix-Loop-Helix Transcription Factor Expressed in Activated B Lymphocytes

Massari, Mark E.; Rivera, Richard; Voland, Joseph R.; Quong, Melanie W.; Breit, Timo M.; Dongen, Jacques J. M. van; Smit, Oncko de; Murre, Cornelis

doi:10.1128/mcb.18.6.3130

Cited by 64 publications

(79 citation statements)

References 79 publications

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“…4a,b). For ABF-1 expressed alone, we observed no binding to any of the probes, consistent with previous observations that ABF-1 normally binds as a heterodimer 20 . In contrast, E47, which is capable of binding as a homodimer 22 , bound the consensus µE5 probe and, more weakly, the LTA+80A probe; no bind- ing was seen for LTA+80C.…”

supporting

confidence: 78%

“…Expression plasmids used were pHBA.FLAG-ABF-1 (ref. 20 Nuclear extracts, EMSAs, western blotting and antibodies. We annealed oligonucleotide probes (sequences are available on request) and used Klenow to radioactively label the resulting oligoduplexes LTA+80C, LTA+80A, LTA+368G, LTA+368C, LTA-293G, LTA-293A, Oct-1 and µE5 with [α 32 P]dCTP (Amersham Pharmacia Biotech).…”

Section: Methodsmentioning

confidence: 99%

“…This commonly occurring haplotype is uniquely defined by two markers, one of which, LTA+80, was found in vitro to modulate allele-specific binding of two E-box binding proteins, ABF-1 and AP-4, in the presence of the LTA+80A allele. ABF-1 is a recently described transcription factor that has been particularly associated with lymphoid tissue 20,23 , raising the possibility that the functional effects of the LTA+80 polymorphism are tissue-specific. ABF-1 repressed transcription in our reporter gene model when the LTA+80A allele was present, consistent with previous reports that it acts as a transcriptional repressor 20,23 , whereas AP-4 had no effect on allele-specific expression.…”

mentioning

confidence: 99%

“…Complex II was supershifted on EMSA using nuclear extracts from LCLs in the presence of antibodies to ABF-1. ABF-1 is a class II bHLH family member recently identified in LCLs that is specifically expressed in lymphoid tissue 20 . We found no evidence of supershift with antibodies to the usual heterodimeric partner of ABF-1, the bHLH protein E47.…”

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confidence: 99%

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Allele-specific repression of lymphotoxin-α by activated B cell factor-1

2004

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Genetic variation at the human LTA locus, encoding lymphotoxin-α, is associated with susceptibility to myocardial infarction, asthma and other diseases. By detailed haplotypic analysis of the locus, we identified a single-nucleotide polymorphism (SNP) at LTA+80 as a main predictor of LTA protein production by human B cells. We found that activated B-cell factor-1 (ABF-1) binds to this site in vitro and suppresses reporter gene expression, but only in the presence of the LTA+80A allele. Using haplotype-specific chromatin immunoprecipitation, we confirmed that ABF-1 is preferentially recruited to the low-producer allele in vivo. These findings provide a molecular model of how LTA expression may be genetically regulated by allele-specific recruitment of the transcriptional repressor ABF-1.Identifying human DNA polymorphisms that regulate gene expression is essential for understanding the genetic basis of common diseases but is technically challenging. Valuable insights into molecular mechanisms can be derived by in vitro analysis of protein-DNA binding and reporter gene expression, but we have limited tools to interrogate putative regulatory polymorphisms in vivo. Such analysis needs to consider natural chromatin structure and natural haplotypic combinations of polymorphisms. It also must be able to detect small differences in gene expression, which could be crucial for disease susceptibility if a physiologically important mediator is involved.We attempted to address these issues for LTA, an important early mediator of immune and inflammatory responses 1 . Regulation of LTA is finely calibrated to resist dangerous pathogens but not to cause inflammatory damage to the host, as seems to occur in bacterial sepsis 2 and a b Figure 1 LTA protein production is associated with LTA haplotype. (a) Haplotype structure at the LTA locus. SNPs present at an allele frequency >0.1 in the panel of 26 LCLs are shown (minor allele frequencies given in brackets) together with haplotypes (haplotype frequencies shown at the head of the columns). Designations of SNPs refer to the nucleotide position relative to transcriptional start site. Clade A is uniquely defined by LTA+10A, LTA+252G and LTA+723A; clade B is uniquely defined by LTA+80A and LTA+368C; and clade C is uniquely defined by LTA+438(10) and LTA+495C. The frequencies of these main haplotype clades were 0.27, 0.46 and 0.27, respectively. (b) Analysis of LTA production by haplotype pair. A scatter plot of LTA concentration in cell culture supernatant from the panel of LCLs is shown per 10 6 cells, plotted as a symbol representing each cell line together with the geometric mean (horizontal lines). A total of six replicate experiments were done. The cell lines heterozygous with respect to haplotypes A, B and C are shown categorized at a given time point according to the pair of haplotypes present in that cell line (A+B, A+C or B+C). At 24 h after stimulation, cells bearing haplotypes B+C or B+A were associated with significantly lower LTA concentrations than those bearing haploty...

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confidence: 78%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Allele-specific repression of lymphotoxin-α by activated B cell factor-1

2004

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“…There are four E proteins in mammals: E12, E47 (both encoded by E2A), HEB, and E2-2 (11)(12)(13). ABF-1, also known as musculin (MSC), was discovered with a yeast two-hybrid screen of a B cell cDNA library using the bHLH region of E2-2 as bait (14). ABF-1 binds to the Ebox element to form a homodimer or heterodimer with E12 or E47 (14).…”

mentioning

confidence: 99%

Transcription Factor ABF-1 Suppresses Plasma Cell Differentiation but Facilitates Memory B Cell Formation

Chiu

Lin

et al. 2014

The Journal of Immunology

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Ag-primed B cells that result from an immune response can form either memory B cells or Ab-secreting plasma cells; however, the molecular machinery that controls this cellular fate is poorly understood. In this study, we show that activated B cell factor-1 (ABF-1), which encodes a basic helix-loop-helix transcriptional repressor, participates in this regulation. ABF-1 was prevalently expressed in purified memory B cells and induced by T follicular helper cell–mediated signals. ABF-1 expression declined by the direct repression of B lymphocyte–induced maturation protein-1 during differentiation. Ectopic expression of ABF-1 reduced the formation of Ab-secreting cells in an in vitro differentiation system of human memory B cells. Accordingly, knockdown of ABF-1 potentiates the formation of Ab-secreting cells. A transgenic mouse that expresses inducible ABF-1 in a B cell–specific manner was generated to demonstrate that the formation of germinal center and memory B cells was augmented by induced ABF-1 in an immune response, whereas the Ag-specific plasma cell response was dampened. This effect was associated with the ability of ABF-1 to limit cell proliferation. Together, our results demonstrate that ABF-1 facilitates formation of memory B cells but prevents plasma cell differentiation.

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Differential expression of Id genes in multipotent myeloid progenitor cells: Id-1 is induced by early- and late-acting cytokines while Id-2 is selectively induced by cytokines that drive terminal granulocytic differentiation

Cooper

Newburger

1998

J. Cell. Biochem.

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Hematopoietic development is regulated by a complex mixture of cytokine growth factors that guide growth and differentiation of progenitor cell populations at different stages in their development. The genetic programs that drive this process are controlled at the molecular level by the type and number of transcriptional regulators coexpressed in the cell. Both positive- and negative-acting helix-loop-helix transcription factors are expressed during hematopoietic development, with the Id-type transdominant negative regulators controlling the net helix-loop-helix activation potential in the cell at any given time. It has been demonstrated that some of these Id factors are involved in the checkpoint at which undifferentiated progenitor cells make the commitment to terminal maturation. Therefore, we sought to determine whether these Id family factors are selectively induced or extinguished by cytokines that act at different points during hematopoiesis. NFS-60, a myeloid progenitor line that proliferates in response to multiple cytokines, was stimulated by treatment with SCF, IL-3, IL-6, G-CSF, and erythropoietin. Id-1 expression correlated tightly with cellular proliferation: it declined when growth factor stimulation was withdrawn and was quickly induced whenever the cell began to proliferate. The regulation of Id-2 was more complex: its expression was slightly upregulated in factor-deprived cells but only strongly reinduced after extended exposure to cytokines that drive granulocytic differentiation (IL-6, G-CSF, and TGFbeta). These data support a cell-cycle regulatory role for Id-1 in multipotent myeloid progenitor cells and a role for Id-2 during terminal granulocytic differentiation.

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Characterization of ABF-1, a Novel Basic Helix-Loop-Helix Transcription Factor Expressed in Activated B Lymphocytes

Cited by 64 publications

References 79 publications

Allele-specific repression of lymphotoxin-α by activated B cell factor-1

Allele-specific repression of lymphotoxin-α by activated B cell factor-1

Transcription Factor ABF-1 Suppresses Plasma Cell Differentiation but Facilitates Memory B Cell Formation

Differential expression of Id genes in multipotent myeloid progenitor cells: Id-1 is induced by early- and late-acting cytokines while Id-2 is selectively induced by cytokines that drive terminal granulocytic differentiation

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