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Vol. 16, No. 8, pp. 933-947, April 15, 2002
1 Department of Molecular and Cellular Biology, Harvard
University, Cambridge, Massachusetts 02138, USA; 2 The
Netherlands Cancer Institute, Division of Molecular Biology, 1066 CX
Amsterdam, The Netherlands; 3 Ludwig Institute for Cancer
Research, Faculty of Medicine, Imperial College, Norfolk Place, London
W2 1PG, UK
Despite biochemical and genetic data suggesting that E2F and pRB
(pocket protein) families regulate transcription via
chromatin-modifying factors, the precise mechanisms underlying gene
regulation by these protein families have not yet been defined in a
physiological setting. In this study, we have investigated promoter
occupancy in wild-type and pocket protein-deficient primary cells. We
show that corepressor complexes consisting of histone deacetylase
(HDAC1) and mSin3B were specifically recruited to endogenous
E2F-regulated promoters in quiescent cells. These complexes dissociated
from promoters once cells reached late G1, coincident with
gene activation. Interestingly, recruitment of HDAC1 complexes to
promoters depended absolutely on p107 and p130, and required an intact
E2F-binding site. In contrast, mSin3B recruitment to certain promoters
did not require p107 or p130, suggesting that recruitment of this corepressor can occur via E2F-dependent and -independent mechanisms. Remarkably, loss of pRB had no effect on HDAC1 or mSin3B recruitment. p107/p130 deficiency triggered a dramatic loss of E2F4 nuclear localization as well as transcriptional derepression, which is suggested by nucleosome mapping studies to be the result of localized hyperacetylation of nucleosomes proximal to E2F-binding sites. Taken
together, these findings show that p130 escorts E2F4 into the nucleus
and, together with corepressor complexes that contain mSin3B and/or
HDAC1, directly represses transcription from target genes as cells
withdraw from the cell cycle.
[Key Words: E2F; Rb; Sin3; HDAC; chromatin; transcriptional control; cell cycle]
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