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Division of Molecular Genetics, Dana–Farber Cancer Institute and Harvard Medical School, and Department of Biology, Boston University, Boston, MA 02215; and
Program in Immunology and Virology, Department of Molecular Genetics and Microbiology, University of Massachusetts Medical Center, Worcester, MA 01655
Ig heavy chain class switch recombination (CSR) determines the
expression of Ig isotypes. The molecular mechanism of CSR and the
factors regulating this process have remained elusive. Recombination
occurs primarily within switch (S) regions, located upstream of each
heavy chain gene (except C
). These repetitive
sequences contain consensus DNA-binding sites for the DNA-binding
protein late SV40 factor (LSF) (CP2/leader-binding protein-1c).
In this study, we demonstrate by EMSA that purified rLSF, as well as
LSF within B cell extracts, directly binds both Sµ and S
sequences. To determine whether LSF is involved in regulating CSR, two
different LSF dominant negative variants were stably expressed in the
mouse B cell line I.29 µ, which can be induced to switch from IgM to
IgA. Overexpression of these dominant negative LSF proteins results in
decreased levels of endogenous LSF DNA-binding activity and an increase
in cells undergoing CSR. Thus, LSF represses class switching to IgA. In
agreement, LSF DNA-binding activity was found to decrease in whole cell
extracts from splenic B cells induced to undergo class switching. To
elucidate the mechanism of CSR regulation by LSF, the interactions of
LSF with proteins involved in chromatin modification were tested in
vitro. LSF interacts with both histone deacetylases and the corepressor
Sin3A. We propose that LSF represses CSR by histone deacetylation of
chromatin within S regions, thereby limiting accessibility to the
switch recombination machinery.
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