Functional analysis of the murine IgH enhancer: evidence for negative control of cell-type specificity

Kadesch, Tom; Zervos, Paula; Ruezinsky, Diane

doi:10.1093/nar/14.20.8209

Cited by 122 publications

(88 citation statements)

References 33 publications

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“…In fact when the O site, in con junction with (xE4, is repeated tandemly, it can function as a tissue-specific enhancer (Gerster et al 1987). Fi nally, the sequences flanking the core enhancer are im portant for enhancer repression in inappropriate cells; deletion of these sequences allows the enhancer to func tion in fibroblasts (Imler et al 1987) or kidney cells (Kadesch et al 1986), or in T cells and macrophages as re ported here, even with a wild-type O site. Apparently negative regulation is dominant to the positive-enhancer elements, as fusion of B cells with non-B cells extin guishes enhancer-activated transcription (Junker et al 1988;Zaller et al 1988).…”

Section: Ig Heavy-chain Enhancer Regulationmentioning

confidence: 68%

“…Recently, evidence for the negative regulation of the heavy-chain enhancer has been presented (Kadesch et al 1986;Wasylyk and Wasylyk 1986). Indeed, experiments using deletion mutants within the enhancer suggest that tissue specificity is, at least in part, mediated by se quences that flank the core enhancer and that act to re press enhancer function, that is, removal of these flanking sequences allows enhancer-mediated gene ex pression in fibroblasts (Imler et al 1987).…”

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confidence: 99%

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A developmental-specific factor binds to suppressor sites flanking the immunoglobulin heavy-chain enhancer.

Scheuermann¹,

Chen²

1989

Genes Dev.

108

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We identified a novel nuclear protein, NF-|jiNR, that binds to multiple sites flanking the immunoglobulin heavy-chain enhancer. The expression of NF-|jiNR shows a unique developmental pattern; the activity is present in all cells representing early stages of B-cell development, but is absent from more mature cells that express a high level of immunoglobulin heavy chains. NF-|iNR also is present in most cell lines outside of the B-cell lineage (e.g., T cells, macrophages, and fibroblasts). The binding sites for NF-|jiNR correlate very well with cisacting negative regulatory elements of the heavy-chain enhancer defined previously. Indeed, when the segments bound by NF-^.NR are deleted from the enhancer, it is now found to function as a positive transcription element in T cells and macrophages. Taken together, these results suggest that NF-|jiNR may function as a negative regulator of enhancer function. The observation that the segments bound by NF-ftNR correspond to the segments bound to the nuclear matrix suggests an intriguing model not only of how enhancers might function but also of how negative regulation might occur.

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Section: Ig Heavy-chain Enhancer Regulationmentioning

confidence: 68%

mentioning

confidence: 99%

A developmental-specific factor binds to suppressor sites flanking the immunoglobulin heavy-chain enhancer.

Scheuermann¹,

Chen²

1989

Genes Dev.

108

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“…For example, the E-boxes in the IgH enhancer are nearly identical to the E-boxes in the muscle creatine kinase enhancer, and Myod binds with equally high affinity to both sets of E-boxes in gel shift assays (Kadesch et al, 1986). In addition, Myod can bind and activate the expression of reporter constructs driven by the IgH E-boxes in transient transfection assays.…”

Section: Myod and Chromatin Remodelingmentioning

confidence: 99%

The circuitry of a master switch: Myod and the regulation of skeletal muscle gene transcription

2005

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The cloning of Myod, a master switch for skeletal muscle In 1979, Taylor and Jones demonstrated that treating the mouse fibroblast cell line 10T1/2 with the demethylating agent 5-azacytidine generated clones with a skeletal muscle phenotypeThe expression of Myod is sufficient to convert a fibroblast to a skeletal muscle cell, and, as such, is a model system in developmental biology for studying how a single initiating event can orchestrate a highly complex and predictable response. Recent findings indicate that Myod functions in an instructive chromatin context and directly regulates genes that are expressed throughout the myogenic program, achieving promoter-specific regulation of its own binding and activity through a feed-forward mechanism. These studies are beginning to merge our understanding of how lineage-specific information is encoded in chromatin with how master regulatory factors drive programs of cell differentiation. Summary

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“…The enhancer contains three elements homologous to the core element identified by mutational analysis of the SV40 enhancer, and this footprint maps to the region of the most downstream core site. Previous mutational analysis concluded that these core sites were not required for B cell-specific activity of the enhancer suggesting that PU.1 binding to this site may represent a nonfunctional interaction (35).…”

Section: Analysis Of Mutation M103-mentioning

confidence: 99%

A Three-protein-DNA Complex on a B Cell-specific Domain of the Immunoglobulin μ Heavy Chain Gene Enhancer

Rao

Dang

Tian³

et al. 1997

Journal of Biological Chemistry

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The lymphoid-specific immunoglobulin heavy chain gene intron enhancer ( E) contains multiple binding sites for trans-acting nuclear factors. We have used a combination of in vitro and in vivo assays to reconstruct protein-DNA interactions on a minimal B cell-specific enhancer that contains three motifs, A, B, and E3. Using ETS-domain proteins that transactivate the minimal enhancer in non-lymphoid cells, we show that (i) PU.1 binds coordinately to both A and B sites in vitro and (ii) in the presence of Ets-1, this factor binds to the A site and PU.1 to the B site. Two factors, TFE3 and USF, bind to the E3 element. When the ETS proteins are present together with E3 binding proteins, a threeprotein-DNA complex is generated. Furthermore, we provide evidence for protein-protein interactions between Ets-1 and PU.1 proteins that bind to A and B sites, and between Ets-1 and TFE3 bound to the A and E3 sites. We propose that this domain of the enhancer is assembled into a nucleoprotein complex that contains two tissue-restricted ETS domain proteins that recognize DNA from the same side of the helix and one ubiquitously expressed bHLH-leucine zipper protein that binds between them, recognizing its site from a different side of the helix. The immunoglobulinheavy chain (IgH) gene intron enhancer is a tissue-specific regulatory element that is necessary for expression of the IgH gene (1, 2). Since the proposal of Alt and colleagues of the correlation between transcription and immunoglobulin gene rearrangements (3-5), the enhancer has been considered a likely candidate to be the sequence that regulates rearrangements at this locus. Recently, this hypothesis has been directly verified in mice containing disrupted enhancer alleles (6, 7). Thus, the enhancer is activated at very early stages of B cell differentiation, prior to the onset of D H to J H rearrangements. In addition, experiments in transgenic mice have shown that this enhancer is sufficient to direct expression of heterologous genes in B and T lymphoid cells (8 -11).The enhancer contains binding sites for multiple DNA binding proteins, and tissue-specific activity has been proposed to be the consequence of both positive and negative regulatory proteins. Positive regulation is effected by lymphoid-specific transcription activators, such as those that bind to the A, B (12-15), and octamer elements (16 -18). Negative regulation is effected by proteins found in non-lymphoid cells that may suppress enhancer activity (19 -22), such as those that bind to the E5 site within the enhancer (23, 24). In addition, there are several sites within the enhancer referred to as E motifs. These elements, E1-E5, fit the consensus CANNTG and bind proteins belonging to the basic helix-loop-helix family of transcription factors (25) that are expressed in both lymphoid and nonlymphoid cells. We have previously shown that mutation of either A or B elements abrogates B cell-specific activity of a 170 nucleotide enhancer ( 170) that contains both these elements as well as E1, E3, and E5. Mutati...

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Functional analysis of the murine IgH enhancer: evidence for negative control of cell-type specificity

Cited by 122 publications

References 33 publications

A developmental-specific factor binds to suppressor sites flanking the immunoglobulin heavy-chain enhancer.

A developmental-specific factor binds to suppressor sites flanking the immunoglobulin heavy-chain enhancer.

The circuitry of a master switch: Myod and the regulation of skeletal muscle gene transcription

A Three-protein-DNA Complex on a B Cell-specific Domain of the Immunoglobulin μ Heavy Chain Gene Enhancer

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