Control of Neuronal Gene Transcription and Behavior by the Epigenetic Suppressor Complex G9a/GLP
Epigenetic control of cellular phenotypes is governed by numerous enzymes that contribute to post-synthetic modifications of DNA and associated histone proteins. These modifications facilitate the assembly of protein complexes that regulate gene expression in a highly orchestrated fashion. The importance of epigenetic regulators in brain development and function is supported by the strong association between mental retardation in humans and the aberrant structure or expression of various epigenetic regulators
Using conditional mutagenesis in mice, we found that the histone methyltransferase complex G9a/GLP (Ehmt1/Ehmt2 in humans), which controls gene expression via di-methylation of histone 3 on lysine 9 (H3K9me2), regulates cognition and complex behavior in mice. Postnatal neuron-specific loss of G9a/GLP in mice recapitulates key symptoms of a severe mental retardation syndrome in humans that is associated with the reduced expression of GLP/Ehmt1. In an attempt to unravel the mechanism of G9a/GLP regulated cognition and behavior, we will discuss the nature of gene expression changes associated with the loss of G9a/GLP.
KeywordsMental Retardation Syndrome Methyltransferase Complex Large Ribosomal Subunit Protein Translate Ribosome Affinity Purification Postnatal Forebrain
I would like to thank Paul Greengard and Alexander Tarakhovsky for their support and discussions and Shrihari Sampath, Myriam Heiman, James Surmeier, and Nathaniel Heintz for their contribution to the work. The work was supported by the Deutsche Forschungsgemeinschaft (DFG) and the National Institute on Drug Abuse (NIDA).
- Balemans MC, Huibers MM, Eikelenboom NW, Kuipers AJ, van Summeren RC, Pijpers MM, Tachibana M, Shinkai Y, van Bokhoven H, Van der Zee CE (2010) Reduced exploration, increased anxiety, and altered social behavior: autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice. Behav Brain Res 208:47–55PubMedCrossRefGoogle Scholar
- Kleefstra T, Smidt M, Banning MJ, Oudakker AR, Van Esch H, de Brouwer AP, Nillesen W, Sistermans EA, Hamel BC, de Bruijn D, Fryns JP, Yntema HG, Brunner HG, de Vries BB, van Bokhoven H (2005) Disruption of the gene euchromatin histone methyl transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome. J Med Genet 42:299–306PubMedCrossRefGoogle Scholar
- Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen W, Magee A, Genevieve D, Cormier-Daire V, van Esch H, Fryns JP, Hamel BC, Sistermans EA, de Vries BB, van Bokhoven H (2006) Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum Genet 79:370–377PubMedCrossRefGoogle Scholar
- Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N, van Dooren M, Willemsen MH, Pfundt R, Turner A, Wilson M, McGaughran J, Rauch A, Zenker M, Adam M, Innes M, Davies C, Gonzalez-Meneses Lopez A, Casalone R, Weber A, Brueton LA, Delicado Navarro A, Palomares Bralo M, Venselaar H, Stegmann SP, Yntema HG, van Bokhoven H, Brunner HG (2009) Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 46:598–606PubMedCrossRefGoogle Scholar
- Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H, Shinkai Y (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16:1779–1791PubMedCrossRefGoogle Scholar
- Yatsenko SA, Cheung SW, Scott DA, Nowaczyk MJ, Tarnopolsky M, Naidu S, Bibat G, Patel A, Leroy JG, Scaglia F, Stankiewicz P, Lupski JR (2005) Deletion 9q343 syndrome: genotype-phenotype correlations and an extended deletion in a patient with features of Opitz C trigonocephaly. J Med Genet 42:328–335PubMedCrossRefGoogle Scholar