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J. Biol. Chem., Vol. 282, Issue 13, 9962-9972, March 30, 2007

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Developmental Regulation of Eed Complex Composition Governs a Switch in Global Histone Modification in Brain^*

Se Young Kim¹, Jonathan M. Levenson², Stanley Korsmeyer^¶, J. David Sweatt³, and Armin Schumacher⁴

From the Department of Molecular and Human Genetics and Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030 and the ^¶Howard Hughes Medical Institute, Department of Pathology and Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

Originally discovered as epigenetic regulators of developmental gene expression, the Polycomb (PcG) and trithorax (trxG) group of proteins form distinct nuclear complexes governing post-translational modification of histone tails. This study identified a novel, developmentally regulated interface between Eed and Mll, pivotal constituents of PcG and trxG pathways, respectively, in mouse brain. Although the PcG proteins Eed and EzH2 (Enhancer of Zeste protein-2) engaged in a common complex during neurodevelopment, Eed associated with the trxG protein Mll upon brain maturation. Comprehensive analysis of multiple histone modifications revealed differential substrate specificity of the novel Eed-Mll complex in adult brain compared with the developmental Eed-EzH2 complex. Newborn brain from eed heterozygotes and eed;Mll double heterozygotes exhibited decreased trimethylation at lysine 27 of histone H3, as well as hyperacetylation of histone H4. In contrast, adult hippocampus from Mll heterozygotes was remarkable for decreased acetylation of histone H4, which restored to wild-type levels in eed;Mll double heterozygotes. A physiological role for the Eed-Mll complex in adult brain was evident from complementary defects in synaptic plasticity in eed and Mll mutant hippocampi. These results support the notion that developmental regulation of complex composition bestows the predominant Eed complex with the chromatin remodeling activity conducive for gene regulation during neurodevelopment and adult brain function. Thus, this study suggests dynamic regulation of chromatin complex composition as a molecular mechanism to co-opt constituents of developmental pathways into the regulation of neuronal memory formation in adult brain.

Received for publication, September 11, 2006 , and in revised form, January 12, 2007.

^* This work was supported in part by research grants from the National Institutes of Health (to D. S. and A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by an NIGMS predoctoral training grant from the National Institutes of Health.

² Supported by an NINDS postdoctoral training grant from the National Institutes of Health. Present address: Dept. of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706.

Deceased.

³ Present address: Dept. of Neurobiology, University of Alabama, Birmingham, AL 35294.

⁴ To whom correspondence should be addressed: Dept. of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-6865; Fax: 713-798-8985; E-mail: armins{at}bcm.tmc.edu.

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