Abstract
The immunoglobulin heavy chain (IgH) intronic enhancer stimulates transcription from functional promoters in B lymphocytes but not other cell types. The observation that binding sites for the nuclear factor-mu negative regulator (NF-muNR) enhancer repressor overlap nuclear matrix attachment regions (MARs) in this enhancer has lead to the hypothesis that the cell type specificity of the enhancer might be controlled by regulating nuclear matrix attachment (Scheuermann, R. H., and Chen, U. (1989) Genes & Dev. 3, 1255-1266). To understand the role of MARs in IgH enhancer regulation, we have identified a novel MAR-binding protein, MAR-BP1, from soluble nuclear matrix preparations based on its ability to bind to the MARs associated with the IgH enhancer. Purified MAR-BP1 migrates as a 33-kDa protein, and it can be found in nuclear matrix preparations from a number of different types of lymphoid cell lines. Although specific binding sites have been difficult to localize by chemical or enzymatic footprinting procedures, NF-muNR binding sites are critical for efficient MAR-BP1 binding. Indeed, binding of the IgH enhancer to either intact nuclear matrix preparations or to MAR-BP1 is mutually exclusive to NF-muNR binding. These results are consistent with a model for cell-type specific regulation in which binding of the NF-muNR repressor to the IgH enhancer prevents nuclear matrix attachment in inappropriate cells by interfering with MAR-BP1/enhancer interaction.
Highlights
The immunoglobulin heavy chain (IgH) intronic enhancer stimulates transcription from functional promoters in B lymphocytes but not other cell types
The observation that binding sites for the nuclear factor- negative regulator (NF-NR) enhancer repressor overlap nuclear matrix attachment regions (MARs) in this enhancer has lead to the hypothesis that the cell type specificity of the enhancer might be controlled by regulating nuclear matrix attachment
To understand the role of MARs in IgH enhancer regulation, we have identified a novel MAR-binding protein, MARBP1, from soluble nuclear matrix preparations based on its ability to bind to the MARs associated with the IgH enhancer
Summary
The immunoglobulin heavy chain (IgH) intronic enhancer stimulates transcription from functional promoters in B lymphocytes but not other cell types. The IgH intronic enhancer, located between the JH elements and C, stimulates transcription from promoters in a relatively distance- and orientation-independent manner, and acts as a cell type-specific regulator, being functional in B cells and nonfunctional in non-B cells (for review, see Staudt and Lenardo (1991)). This enhancer contains multiple DNA sequence motifs that function as interaction sites for sequence-specific DNA-binding proteins. Proteins binding to MARs include lamin B1 and topoisomerase II, which are major components of the nuclear matrix (Luderus et al, 1992; Sperry et al, 1989); the yeast RAP-1 factor and HeLa SAF-A/ hnRNP-U, which induce DNA loop formation (Hofmann et al, 1989; Romig et al, 1992; Fackelmayer et al, 1994); and SATB1 and nucleolin, which seems to preferentially bind DNA with base-unpairing potential (Dickinson and Kohwi-Shigematsu, 1995)
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