Nuclear matrix associating regions (MARs) have been implicated in transcriptional control of several genes, including the immunoglobulin heavy chain (IgH). The MARs flanking the IgH intronic enhancer (Em) are the targets of positive and negative regulators identified by this investigator. Both factors partition to the nuclear matrix in cell-type, developmental stage-restricted fashions: The positive regulator in mature/Ig-secreting B cells and the negative regulator in non-B cells. The differential occupancy of these two factors is hypothesized to contribute to enhancer control, perhaps by regulating nuclear matrix attachment and/or chromatin structure. In this model the MARs function as a genetic switch, contributing to Em activation in B cells and Em repression in non-B cells. Through a series of biochemical and genetic approaches the investigator proposes to further characterize these factors and their MAR interactions, to study the mechanism of the proposed switch, and to understand the consequences upon B cell lineage development and differentiation.
In Aim 1 the structure, function and expression of Bright will be further characterized.
In Aim 2 a similar analysis will be performed on the Cux and 40kd proteins.
In Aim 3 the mechanism of the genetic switch involving these factors, and the role of MARs in this process will be investigated.
In Aim 4 the consequences of the genetic switch on Emu cell type restriction and B lineage development will be investigated.
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