Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
PLoS Biol. 2011 Jan 4;9(1):e1000569. doi: 10.1371/journal.pbio.1000569.
The epigenetic modification of chromatin structure and its effect on complex neuronal processes like learning and memory is an emerging field in neuroscience. However, little is known about the "writers" of the neuronal epigenome and how they lay down the basis for proper cognition. Here, we have dissected the neuronal function of the Drosophila euchromatin histone methyltransferase (EHMT), a member of a conserved protein family that methylates histone 3 at lysine 9 (H3K9). EHMT is widely expressed in the nervous system and other tissues, yet EHMT mutant flies are viable. Neurodevelopmental and behavioral analyses identified EHMT as a regulator of peripheral dendrite development, larval locomotor behavior, non-associative learning, and courtship memory. The requirement for EHMT in memory was mapped to 7B-Gal4 positive cells, which are, in adult brains, predominantly mushroom body neurons. Moreover, memory was restored by EHMT re-expression during adulthood, indicating that cognitive defects are reversible in EHMT mutants. To uncover the underlying molecular mechanisms, we generated genome-wide H3K9 dimethylation profiles by ChIP-seq. Loss of H3K9 dimethylation in EHMT mutants occurs at 5% of the euchromatic genome and is enriched at the 5' and 3' ends of distinct classes of genes that control neuronal and behavioral processes that are corrupted in EHMT mutants. Our study identifies Drosophila EHMT as a key regulator of cognition that orchestrates an epigenetic program featuring classic learning and memory genes. Our findings are relevant to the pathophysiological mechanisms underlying Kleefstra Syndrome, a severe form of intellectual disability caused by mutations in human EHMT1, and have potential therapeutic implications. Our work thus provides novel insights into the epigenetic control of cognition in health and disease.
染色质结构的表观遗传修饰及其对学习和记忆等复杂神经元过程的影响是神经科学中的一个新兴领域。然而，人们对神经元表观基因组的“书写者”以及它们如何为正常认知奠定基础知之甚少。在这里，我们剖析了果蝇常染色质组蛋白甲基转移酶（EHMT）的神经元功能，EHMT 是一种保守蛋白家族的成员，它在赖氨酸 9 上甲基化组蛋白 3（H3K9）。EHMT 在神经系统和其他组织中广泛表达，但 EHMT 突变体果蝇是存活的。神经发育和行为分析将 EHMT 鉴定为外围树突发育、幼虫运动行为、非联想学习和求偶记忆的调节剂。EHMT 在记忆中的需求被映射到 7B-Gal4 阳性细胞，这些细胞在成年大脑中主要是蘑菇体神经元。此外，通过成年期 EHMT 的重新表达来恢复记忆，表明 EHMT 突变体中的认知缺陷是可逆的。为了揭示潜在的分子机制，我们通过 ChIP-seq 生成了全基因组 H3K9 二甲基化图谱。EHMT 突变体中 H3K9 二甲基化的缺失发生在常染色质基因组的 5%，并且在控制神经元和行为过程的不同类别的基因的 5'和 3' 末端富集，这些过程在 EHMT 突变体中受到破坏。我们的研究将果蝇 EHMT 鉴定为认知的关键调节剂，它协调了一个以经典学习和记忆基因为特征的表观遗传程序。我们的发现与 Kleefstra 综合征的病理生理机制有关，Kleefstra 综合征是一种由人类 EHMT1 突变引起的严重智力残疾形式，并且具有潜在的治疗意义。我们的工作因此为健康和疾病中的认知的表观遗传控制提供了新的见解。
