Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 18, Pages 7541-7546Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1017374108
Keywords
histone methylation; breast cancer
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Funding
- National Natural Science Foundation of China [30830032, 30921062, 81071673]
- Ministry of Science and Technology of China [2011CB504204, 2007-CB914503, 2009CB918903]
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It is well-documented that the methylation of histone H3 lysine 4 (H3K4) and of H3K9 are mutually exclusive, an epigenetic phenomenon conserved from yeast to humans. How this opposed methylation modification is accomplished and coordinated in mammalian cells is poorly understood. Here we report that the H3K9 trimethyl demethylase JMJD2B is an integral component of the H3K4-specific methyltransferase, the mixed-lineage leukemia (MLL) 2 complex. We show that the JMJD2B/MLL2 complex is copurified with estrogen receptor alpha (ER alpha) and is required for ER alpha-regulated transcription. We demonstrate that H3K9 demethylation and H3K4 methylation are coordinated in ER alpha-activated transcription such that H3K9 demethylation is a prerequisite for H3K4 methylation. Significantly, depletion of JMJD2B impairs the estrogen-induced G(1)/S transition of the cell cycle in vitro and inhibits breast tumorigenesis in vivo. Interestingly, JMJD2B itself is an ER alpha target gene, and forms a feed-forward regulatory loop in regulation of the hormone response. Our results provide a molecular basis for the coordinated H3K4 methylation/H3K9 demethylation in transcription activation, link the trimethyl demethylase JMJD2B to euchromatin functions, and provide a mechanism for JMJD2B in breast carcinogenesis.
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