Nucleic Acids Research, Vol 24, Issue 24 5034-5044, Copyright © 1996 by Oxford University Press
TL Haynes, MB Thomas, MR Dusing, MT Valerius, SS Potter and DA Wiginton
Transcriptional activation of eukaryotic genes involves assembly of
specific multiprotein complexes on the promoters and enhancers of the
genes. Recently, it has been proposed that the role of some of the proteins
in the complex may be architectural, involving DNA bending, orchestration
of protein-protein interaction and modulation of nucleosome structure. This
role has been proposed for the HMG proteins LEF-1 and TCF-1. We examined
the role of a LEF-1/TCF-1 binding site in the human adenosine deaminase
(ADA) thymic enhancer. Mutational analysis demonstrated that a functional
LEF-1/TCF-1 binding site is not required for enhancer-mediated
transcriptional activation in transient transfection studies, but is
essential for enhancer function in the in vivo chromatin context of
transgenic mice. Mutation of the LEF-1/TCF-1 site destroyed the ability of
the ADA enhancer/locus control region to specify high level, insertion
site-independent transgene expression in thymus. DNase I and DpnII
accessibility experiments indicated dramatic changes in the chromatin
organization of the ADA enhancer in transgenic mice with a mutated
LEF-1/TCF-1 site. This supports the hypothesis that factors binding the
LEF-1/TCF-1 site play an architectural role during the in vivo activation
of the ADA enhancer, possibly involving chromatin modification.
ARTICLES
An enhancer LEF-1/TCF-1 site is essential for insertion site- independent transgene expression in thymus
Department of Pediatrics, University of Cincinnati, OH 45229, USA.
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