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.

生物学的主要技术突破揭示了我们的新维度了解基因调节和染色质3-D结构。核心理解基因调节是转录调节的研究的研究从增强器转录的RNA（lncRNA）。而lncrnas的概念现在接受了转录调节剂，扮演全基因组角色，该关系 LNCRNA和染色质3-D结构之间仍不清楚。因此，中央生物学中的问题仍然存在：LNCRNA如何与染色质相互作用以建立基因调节网络在染色质3-D结构的背景下？通过结合大规模分析，包括下一代核酸测序，质谱蛋白测序，全基因组染色体构象和生物信息学，我们现在可以研究这种关系在表观遗传因子，基因调节和染色质3-D结构之间。十多年来，我的实验室一直在研究EVF2的转录调节，第一个增强子调节，超保存的lncRNA（Feng等，2006； Bond等，2009， Berghoff等。 2013年，Cajigas等。 2015）。这些研究共同确定了一些关于LNCRNA在基因调节中的作用的基本原则，包括发现单个发育调节的lncRNA控制着gabaergic interneuron 发展和成人脑电路（Bond等，2009）。我们以前的工作着重于 EVF2对相邻或重叠的DLX5/6基因间增强剂的调节，并报告短期对基因表达，转录因子募集，组蛋白的影响修改，位点特异性CpG DNA甲基化以及直接抑制ATPase和染色质重塑活性（Bond等，2009； Berghoff等，2013，Cajigas等。 2015）。在此提案中，我们将结合在此中开发的遗传和生化工具过去十年中，我的实验室以及最近的大型技术来确定 EVF2基因调节网络与染色质3-D结构之间的关系。