The enhancer landscape during early neocortical development reveals patterns of dense regulation and co-option.
The enhancer landscape during early neocortical development reveals patterns of dense regulation and co-option.
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DOI：
10.1371/journal.pgen.1003728
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发表时间：
2013-08
期刊：
影响因子：
4.5
通讯作者：
Bejerano G
中科院分区：
文献类型：
--
作者：
Wenger AM;Clarke SL;Notwell JH;Chung T;Tuteja G;Guturu H;Schaar BT;Bejerano G
遗传学研究已经确定了一组控制新皮质发育的核心转录因子和靶基因，新皮质是人脑中负责高级认知的区域。这些因素、许多关键的上游和下游基因以及介导所有这些相互作用的增强子之间的具体调控相互作用仍然大多未知。我们进行 p300 ChIP-seq 来鉴定在胚胎 14.5 天 (E14.5) 小鼠的背脑壁中活跃的 6,600 多个候选增强子。我们测量的 95% 以上的峰是人类保守的。十名候选者中的八名（80%）使用小鼠转基因驱动新皮质内受限层状模式的活动进行测试。基于 GREAT 的计算分析揭示了与新皮质发育关键区域中 E14.5 表达的基因高度显着的相关性，并允许根据已知的生物功能和途径对增强子进行分组以供进一步研究。我们发现多个基因的两侧各有数十个候选增强子，包括众所周知的关键新皮质基因以及可疑的和新的基因。我们的候选增强子中近四分之一的保守性远远超出哺乳动物。与我们的候选增强子同源的人类和斑马鱼区域被证明最常在中枢神经系统发育的其他方面发挥作用。最后，我们发现强有力的证据表明，特定的散布重复家庭通过共同选择贡献了潜在的关键发育促进剂。我们的分析扩展了可用于提取全基因组功能图谱中丰富信息的方法。基于测序的技术提供了转录调控的全局快照。这些数据有望深入了解基因调控、疾病易感性和生物体进化。它们还为从大量数据中提取特定假设提出了方法论挑战。迄今为止，大多数工作都集中在获得广泛的生化见解。在这里，我们获得了早期新皮质发育过程中背侧大脑壁的主动增强子景观。我们表明，我们的集合可能包含来自正在发育的新皮质、心室、心室下和中间区的增强子，并开发了在特定情况下将这些质量分成感兴趣的子集的方法。我们在关键的新皮质发育基因旁边发现了新的增强子。我们表明，一些已知的关键和新基因各自受到数十个增强子的调节，并在我们的组中找到了关键转录因子的已知和新的富集结合位点。几乎所有新发现的增强子在人类中都是保守的。四分之一的基因座与非哺乳动物脊椎动物共享。我们表明，我们的增强子的人类和斑马鱼直系同源物主要驱动相关神经系统环境中的表达。我们还表明，特定的散布重复序列优先被纳入潜在的关键新皮质发育增强子中。
Genetic studies have identified a core set of transcription factors and target genes that control the development of the neocortex, the region of the human brain responsible for higher cognition. The specific regulatory interactions between these factors, many key upstream and downstream genes, and the enhancers that mediate all these interactions remain mostly uncharacterized. We perform p300 ChIP-seq to identify over 6,600 candidate enhancers active in the dorsal cerebral wall of embryonic day 14.5 (E14.5) mice. Over 95% of the peaks we measure are conserved to human. Eight of ten (80%) candidates tested using mouse transgenesis drive activity in restricted laminar patterns within the neocortex. GREAT based computational analysis reveals highly significant correlation with genes expressed at E14.5 in key areas for neocortex development, and allows the grouping of enhancers by known biological functions and pathways for further studies. We find that multiple genes are flanked by dozens of candidate enhancers each, including well-known key neocortical genes as well as suspected and novel genes. Nearly a quarter of our candidate enhancers are conserved well beyond mammals. Human and zebrafish regions orthologous to our candidate enhancers are shown to most often function in other aspects of central nervous system development. Finally, we find strong evidence that specific interspersed repeat families have contributed potentially key developmental enhancers via co-option. Our analysis expands the methodologies available for extracting the richness of information found in genome-wide functional maps. Sequencing based technologies provide global snapshots of transcriptional regulation. These data promise insights into gene regulation, disease susceptibility and organismal evolution. They also provide a methodological challenge in distilling specific hypotheses from large masses of data. Most work to date has focused on deriving broad biochemical insights. Here we obtain the active enhancer landscape of the dorsal cerebral wall during early neocortical development. We show that our set likely contains enhancers from both the developing neocortex, the ventricular, subventricular and intermediate zones, and develop methods to separate this mass into subsets of interest in particular contexts. We discover novel enhancers next to key neocortex development genes. We show that some known key and novel genes are regulated by dozens of enhancers each, and find known and novel enriched binding sites for key transcription factors in our set. Nearly all newly discovered enhancers are conserved in human. A quarter of loci are shared with non-mammalian vertebrates. We show that the human and zebrafish orthologs of our enhancers mostly drive expression in related nervous system contexts. We also show that particular interspersed repeats were preferentially co-opted into potentially key neocortex development enhancers.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Finger JH;Smith CM;Hayamizu TF;McCright IJ;Eppig JT;Kadin JA;Richardson JE;Ringwald M
通讯作者：
Ringwald M
影响因子：
14.9
作者：
GRONOSTAJSKI, RM
通讯作者：
GRONOSTAJSKI, RM
DOI：
10.1073/pnas.1002285107
发表时间：
2010-07-20
影响因子：
11.1
作者：
Bedogni, Francesco;Hodge, Rebecca D.;Hevner, Robert F.
通讯作者：
Hevner, Robert F.
影响因子：
56.9
作者：
Bailey, JA;Gu, ZP;Eichler, EE
通讯作者：
Eichler, EE