Sandstrom Richard S, Foret Michael R, Grow Douglas A, Haugen Eric, Rhodes Christopher T, Cardona Astrid E, Phelix Clyde F, Wang Yufeng, Berger Mitchel S, Lin Chin-Hsing Annie
Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, USA.
Sci Rep. 2014 Jun 20;4:5371. doi: 10.1038/srep05371.
Histone 3 lysine 4 trimethylation (H3K4me3) is known to be associated with transcriptionally active or poised genes and required for postnatal neurogenesis within the subventricular zone (SVZ) in the rodent model. Previous comparisons have shown significant correlation between baboon (Papio anubis) and human brain. In this study, we demonstrate that chromatin activation mark H3K4me3 is present in undifferentiated progenitor cells within the SVZ of adult baboon brain. To identify the targets and regulatory role of H3K4me3 within the baboon SVZ, we developed a technique to purify undifferentiated SVZ cells while preserving the endogenous nature without introducing culture artifact to maintain the in vivo chromatin state for genome-wide studies (ChIP-Seq and RNA-Seq). Overall, H3K4me3 is significantly enriched for genes involved in cell cycle, metabolism, protein synthesis, signaling pathways, and cancer mechanisms. Additionally, we found elevated levels of H3K4me3 in the MRI-classified SVZ-associated Glioblastoma Multiforme (GBM), which has a transcriptional profile that reflects the H3K4me3 modifications in the undifferentiated progenitor cells of the baboon SVZ. Our findings highlight the importance of H3K4me3 in coordinating distinct networks and pathways for life-long neurogenesis, and suggest that subtypes of GBM could occur, at least in part, due to aberrant H3K4me3 epigenetic regulation.
组蛋白3赖氨酸4三甲基化（H3K4me3）已知与转录活跃或处于就绪状态的基因相关，并且在啮齿动物模型的脑室下区（SVZ）产后神经发生中是必需的。先前的比较表明狒狒（埃及狒狒）和人类大脑之间存在显著相关性。在本研究中，我们证明染色质激活标记H3K4me3存在于成年狒狒大脑SVZ内的未分化祖细胞中。为了确定狒狒SVZ内H3K4me3的靶标和调控作用，我们开发了一种技术，可纯化未分化的SVZ细胞，同时保留内源性，不引入培养假象以维持体内染色质状态用于全基因组研究（ChIP-Seq和RNA-Seq）。总体而言，H3K4me3在参与细胞周期、代谢、蛋白质合成、信号通路和癌症机制的基因中显著富集。此外，我们发现MRI分类的与SVZ相关的多形性胶质母细胞瘤（GBM）中H3K4me3水平升高，其转录谱反映了狒狒SVZ未分化祖细胞中的H3K4me3修饰。我们的研究结果突出了H3K4me3在协调终身神经发生的不同网络和途径中的重要性，并表明GBM的亚型可能至少部分是由于异常的H3K4me3表观遗传调控而发生的。
