Transcriptional control of Hedgehog/Gli target enhancers

Hedgehog/Gli 靶增强子的转录控制

• 批准号: 9923721
• 负责人: Scott Barolo
• 金额: $ 33.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923721
• 关键词: Address; Adult; Affect; Affinity; Animal Model; Animals; Architecture; Automobile Driving; Binding; Biological Models; Cell Fate Control; Cell Survival; Cell physiology; Cells; Characteristics; Collaborations; Complex; Critical Pathways; Cultured Cells; DNA; DNA Sequence; Data; Development; Disease; Drosophila genus; Enhancers; Erinaceidae; Evolution; Family; Feedback; Gene Activation; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Diseases; Genetic Transcription; Genetic Variation; Genome; Genomics; Health; Homeostasis; Human; Human Genetics; Intuition; Laboratories; Learning; Logic; Malignant Neoplasms; Mammals; Mediating; Modeling; Morphology; Mus; Mutate; Organ; Organism; Participant; Pathway interactions; Pattern; Physiological; Play; Population; Prevention; Production; Protein Isoforms; Regulation; Regulator Genes; Regulatory Element; Repression; Research; Role; Signal Pathway; Signal Transduction; Site; System; Testing; Time; Tissues; Transcriptional Regulation; Translating; Untranslated RNA; Variant; Vertebrates; Work; adult stem cell; cell motility; fly; genome-wide; genomic locus; genomic variation; human disease; in vivo; intercellular communication; mouse development; receptor; response; smoothened signaling pathway; stem cells; tool; transcription factor

Abstract Cell-cell signaling pathways control the fate of cells during development and in adult stem cell contexts, and are frequently mis-regulated in disease states. Hedgehog, an ancient and highly conserved signaling pathway with many roles in animal development and homeostasis, controls the activity of Gli transcription factors, which then bind to sites within enhancers, or cis- regulatory elements, in the genome to influence the transcription of pathway target genes. Enhancers integrate spatial, temporal, physiological, and lineage information to control the pattern, timing, and levels of gene expression. Enhancer sequences account for a large proportion of disease-associated genomic variation in human populations. Investigating the mechanisms by which signal-regulated enhancers control gene expression helps us understand how organisms, tissues, and organs self-assemble during development, how they are maintained in adulthood, how they go awry in disease, and how new features are acquired and modified in the course of evolution. New tools for studying gene regulation at a detailed, mechanistic level have been developed over the past several years: these tools, combined with more established experimental approaches, provide opportunities to ask fundamental questions about how the regulatory genome functions and evolves. This highly collaborative project takes advantage of the remarkable conservation of the Hedgehog/Gli pathway with a multi-organismal approach, focusing on regulatory mechanisms that are common to fruit fly, chick, and mouse development, and benefiting from the experimental strengths of each of these model systems. The proposed project will combine fly and vertebrate model systems to accomplish three objectives: (1) Determine how Gli binding motifs in DNA, and common Gli motif variants, control the expression of Hedgehog target genes; (2) Investigate competition for occupancy of Gli binding motifs as a transcriptional regulatory mechanism; and (3) Decode the cis-regulatory logic of developmental Hedgehog/Gli target enhancers in flies and vertebrates.

摘要 细胞-细胞信号通路控制着细胞在发育和成体干细胞中的命运 在某些情况下，它经常在疾病状态下被错误调节。刺猬，一种古老而高度 保守的信号通路在动物发育和体内平衡中具有许多作用， Gli转录因子的活性，然后结合到增强子内的位点，或顺式- 调控元件，以影响途径靶基因的转录。 增强子整合了空间、时间、生理和谱系信息以控制细胞的生长。 基因表达的模式、时间和水平。增强子序列占大的 疾病相关基因组变异在人群中的比例。调查 信号调节增强子控制基因表达的机制有助于我们理解 生物体、组织和器官在发育过程中如何自我组装， 在成年期维持，他们如何在疾病中出错，以及如何获得新的功能， 在进化过程中被改变。研究基因调控的新工具， 在过去的几年里，机械水平已经发展起来：这些工具，结合 更成熟的实验方法，提供了提出基本问题的机会， 关于调控基因组是如何运作和进化的。 这个高度合作的项目利用了 Hedgehog/Gli途径与多生物体方法，重点是调节机制 这是常见的果蝇，小鸡，和小鼠的发展，并受益于 这些模型系统中的每一个的实验强度。拟议的项目将联合收割机飞行 和脊椎动物模型系统，以实现三个目标：（1）确定如何Gli结合 DNA中的基序和常见的Gli基序变体控制Hedgehog靶标的表达。 （2）研究Gli结合基序作为转录因子的占用竞争; （3）解码发育Hedgehog/Gli的顺式调控逻辑 在果蝇和脊椎动物中的靶向增强子。

项目成果

Spatial regulation by multiple Gremlin1 enhancers provides digit development with cis-regulatory robustness and evolutionary plasticity.

• DOI: 10.1038/s41467-021-25810-1
• 发表时间: 2021-09-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Malkmus J;Ramos Martins L;Jhanwar S;Kircher B;Palacio V;Sheth R;Leal F;Duchesne A;Lopez-Rios J;Peterson KA;Reinhardt R;Onimaru K;Cohn MJ;Zuniga A;Zeller R
• 通讯作者: Zeller R