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A Histone Methyltransferase Is Required for Maximal Response to Female Sex Hormones

Tobias Carling,^1,2, Keun-Cheol Kim,^1, Xiao-Hong Yang,¹ Jian Gu,¹ Xiao-Kun Zhang,¹ and Shi Huang^1*

The Burnham Institute, La Jolla, California 92037,¹ Department of Surgery, Uppsala University Hospital, SE-751 85 Uppsala, Sweden²

Received 24 November 2003/ Returned for modification 6 January 2004/ Accepted 25 May 2004

RIZ1 is an estrogen receptor (ER) coactivator but is also a histone lysine methyltransferase that methylates lysine 9 of histone H3, an activity known to repress transcription. We show here that target organs of mice deficient in RIZ1 exhibit decreased response to female sex hormones. RIZ1 interacted with SRC1 and p300, suggesting that the coactivator function of RIZ1 may be mediated by its interaction with other transcriptional coactivators. In the presence of estrogen, RIZ1 binding to estrogen target genes became less direct and followed the binding of ER to DNA and RIZ1 methyltransferase activity on H3-Lys 9 was inhibited, indicating derepression may play a role in estrogen induction of gene transcription. Reducing RIZ1 level correlated with decreased induction of pS2 gene by estrogen in MCF7 cells. The data suggest that a histone methyltransferase is required for optimal estrogen response in female reproductive tissues and that estrogen-bound ER may turn a transcriptional repressor into a coactivator.

T.C. and K.-C.K. contributed equally to this study.

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