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Originally published In Press as doi:10.1074/jbc.M212203200 on January 2, 2003

J. Biol. Chem., Vol. 278, Issue 11, 9514-9519, March 14, 2003
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Bidirectional Silencing and DNA Methylation-sensitive Methylation-spreading Properties of the Kcnq1 Imprinting Control Region Map to the Same Regions*

Noopur ThakurDagger §, Meena KanduriDagger §, Claes HolmgrenDagger , Rituparna MukhopadhyayDagger , and Chandrasekhar KanduriDagger

From the Dagger  Department of Development and Genetics, Evolution Biology Centre, Uppsala University, Norbyvägen 18A, S-752 36 Uppsala, Sweden

The mechanisms underlying the phenomenon of genomic imprinting are poorly understood. Accumulating evidence suggests that imprinting control regions (ICR) associated with the imprinted genes play an important role in creation of imprinted expression domains by propagating parent-of-origin-specific epigenetic modifications. We have recently documented that the Kcnq1 ICR unidirectionally blocks enhancer-promoter communications in a methylation-dependent manner in Hep-3B and Jurkat cell lines. In this report we show that the Kcnq1 ICR harbors bidirectional silencing and methylation-sensitive methylation-spreading properties in a lineage-specific manner. We fine map both of these functions to two critical regions, and loss of one these regions results in loss of silencing as well as methylation spreading. The cell type-specific functions of the Kcnq1 ICR suggest binding of cell type-specific factors to various cis elements within the ICR. Fine mapping of the silencing and methylation-spreading functions to the same regions explains the fact that the silencing factors associated with this region primarily repress the neighboring genes and that methylation occurs as a consequence of silencing.

* This work was partially funded by Vonhofsten Foundation and Helge AX:SON Johnsons Stiftelse (to C. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ N. T. and M. K. contributed equally to this work.

To whom correspondence should be addressed. E-mail: kanduri.chandrasekhar@ebc.uu.se.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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