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Mechanisms regulating lncRNA short and long range signaling

lncRNA短程和长程信号传导的调节机制

基本信息

批准号：
9901574
负责人：
Jhumku Dutt Kohtz
金额：
$ 52.62万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-24 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901574
关键词：
3-Dimensional ATP phosphohydrolase Adult Affect Binding Biochemistry Bioinformatics Biology Brain Chromatin Chromosome 6 Chromosomes DNA DNA Methylation Data Development Dimensions Embryo Enhancers Epigenetic Process Epilepsy Fluorescent in Situ Hybridization Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Models Genetic Transcription Grant Heart Histone Acetylation Individual Institutes Intellectual functioning disability Interneuron function Interneurons Link Mass Spectrum Analysis Molecular Molecular Conformation Mus Nucleic acid sequencing Nucleosomes Peptide Sequence Determination Play Positioning Attribute Proteins RNA Regulation Regulator Genes Reporting Ribonucleoproteins Role SMARCA4 gene Schizophrenia Signal Transduction Site Sleep System Technology Transcript Transcriptional Regulation Transgenes Untranslated RNA Work autism spectrum disorder biochemical tools brain circuitry brain tissue chromatin remodeling epigenetic regulation genome-wide histone modification member mouse genetics neuropsychiatric disorder next generation novel recruit three dimensional structure transcription factor

项目摘要

Major technological breakthroughs in biology reveal new dimensions in our understanding of gene regulation and chromatin 3-D structure. At the heart of understanding gene regulation are studies of transcription-regulating, long non-coding RNAs (lncRNAs) that are transcribed from enhancers. While the concept that lncRNAs play genome-wide roles as transcriptional regulators is now accepted, the relationship between lncRNAs and chromatin 3-D structure is still unclear. Therefore, a central question in biology remains: How do lncRNAs interact with chromatin to establish gene regulatory networks in the context of chromatin 3-D structure? By using a combination of large-scale analyses, including next-generation nucleic-acid sequencing, mass spectrometry protein sequencing, genome-wide chromosome conformation, and bioinformatics, we can now investigate the relationship between epigenetic factors, gene regulation, and chromatin 3-D structure. For over a decade, my lab has been studying transcriptional regulation by Evf2, the first enhancer-regulating, ultraconserved lncRNA (Feng et al. 2006, Bond et al. 2009, Berghoff et al. 2013, Cajigas et al. 2015). Collectively, these studies establish some fundamental principles regarding the role of lncRNAs in gene regulation, including the finding that a single developmentally regulated lncRNA controls GABAergic interneuron development and adult brain circuitry (Bond et al. 2009). Our previous work focused on Evf2 regulation of adjacent or overlapping, Dlx5/6 intergenic enhancers, and reported short-range effects on gene expression, transcription factor recruitment, histone modifications, site-specific CpG DNA methylation, and direct inhibition of ATPase and chromatin remodeling activities (Bond et al. 2009, Berghoff et al. 2013, Cajigas et al. 2015). In this proposal, we will combine the genetic and biochemical tools developed in my lab over the past decade, with recent large-scale technologies, to determine the relationship between the Evf2 gene regulatory network and chromatin 3-D structure.

生物学上的重大技术突破揭示了我们人类了解基因调控和染色质三维结构。的核心理解基因调控是研究转录调控，长非编码从增强子转录的RNA（lncRNA）。虽然lncRNA的概念作为转录调节因子在全基因组范围内发挥作用， lncRNA与染色质三维结构之间的关系尚不清楚。因此，一个中央生物学中的一个问题仍然存在：lncRNA如何与染色质相互作用，染色质三维结构背景下的基因调控网络？通过使用大规模分析的组合，包括下一代核酸测序，质谱，蛋白质测序，全基因组染色体构象和生物信息学，我们现在可以研究表观遗传因素、基因调控和染色质三维结构之间的联系。十多年来，我的实验室一直在研究Evf 2的转录调控，第一个增强子调节的超保守lncRNA（Feng等2006，Bond等2009， Berghoff等人，2013年; Cajigas等人，2015年）。总的来说，这些研究建立了一些关于lncRNA在基因调节中作用的基本原则，包括发现单个发育调节的lncRNA控制GABA能中间神经元发育和成人脑回路（Bond et al. 2009）。我们以前的工作集中在 Evf 2调节相邻或重叠的Dlx 5/6基因间增强子，并报道对基因表达、转录因子募集、组蛋白修饰、位点特异性CpG DNA甲基化和ATP酶的直接抑制，染色质重塑活性（Bond et al. 2009，Berghoff et al. 2013，Cajigas et al. 2015年）。在这个提议中，我们将联合收割机结合在我的实验室在过去的十年里，与最近的大规模技术，以确定 Evf 2基因调控网络与染色质三维结构之间的关系。