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Vol. 15, No. 14, pp. 1817-1832, July 15, 2001
1 Howard Hughes Medical Institute, Department of
Microbiology, Immunology, and Molecular Genetics, and Molecular Biology
Institute, University of California, Los Angeles, California
90095-1662, USA; 2 Lymphocyte Development Group, MRC Clinical
Sciences Centre, Imperial College School of Medicine, Hammersmith
Hospital, London W12 ONN, UK
Ikaros is a unique regulator of lymphopoiesis that associates with
pericentromeric heterochromatin and has been implicated in heritable
gene inactivation. Binding and competition experiments demonstrate that
Ikaros dimers compete with an Ets activator for occupancy of the
lymphocyte-specific TdT promoter. Mutations that selectively disrupt
Ikaros binding to an integrated TdT promoter had no effect on promoter
function in a CD4+CD8+ thymocyte line. However,
these mutations abolished down-regulation on differentiation, providing
evidence that Ikaros plays a direct role in repression. Reduced access
to restriction enzyme cleavage suggested that chromatin alterations
accompany down-regulation. The Ikaros-dependent down-regulation event
and the observed chromatin alterations appear to precede
pericentromeric repositioning. Current models propose that the
functions of Ikaros should be disrupted by a small isoform that retains
the dimerization domain and lacks the DNA-binding domain. Surprisingly,
in the CD4+CD8+ thymocyte line, overexpression of a
small Ikaros isoform had no effect on differentiation or on the
pericentromeric targeting and DNA-binding properties of Ikaros. Rather,
the small isoform assembled into multimeric complexes with DNA-bound
Ikaros at the pericentromeric foci. The capacity for in vivo multimer
formation suggests that interactions between Ikaros dimers bound to the TdT promoter and those bound to pericentromeric repeat sequences may
contribute to the pericentromeric repositioning of the inactive gene.
[Key Words: Ikaros; TdT; lymphocytes; transcription]
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