Mapping and prediction of quantitative transcription factor dosage effects to understand variation in craniofacial morphology and disease

定量转录因子剂量效应的绘图和预测，以了解颅面形态和疾病的变化

• 批准号: 10641572
• 负责人: Sahin Naqvi
• 金额: $ 12.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641572
• 关键词: ATAC-seq; Advisory Committees; Alleles; Automobile Driving; Binding; Biological; Biological Assay; Buffers; Cephalic; Characteristics; Chemicals; Chromatin; Cleft Palate; Communities; Complex; Congenital Abnormality; Data; Data Set; Defect; Development; Developmental Gene; Developmental Process; Disease; Dose; Educational workshop; Ensure; Environment; Face; Faculty; Feedback; Gene Dosage; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Grant; Human; Human Genetics; In Vitro; Individual; Jaw; Knock-out; Learning; MSX1 gene; Machine Learning; Mandible; Maps; Measurement; Mediating; Mentors; Modeling; Molecular; Morphology; Mutation; Nature; Neural Crest Cell; Normal Range; Occupations; PAX3 gene; Pathway interactions; Phase; Phenotype; Pierre Robin Syndrome; Play; Population; Positioning Attribute; Postdoctoral Fellow; Proliferating; Proteins; Publications; Publishing; Rare Diseases; Regulation; Regulator Genes; Regulatory Element; Reporter; Research; Resources; Role; Skeleton; Syndrome; System; Systems Biology; TFAP2B gene; TWIST1 gene; Testing; Training; Transcriptional Regulation; Translating; Untranslated RNA; Variant; Work; Writing; blastomere structure; brain shape; career; career development; cell motility; craniofacial; craniofacial development; craniofacial disorder; deep learning; disorder risk; dosage; embryo cell; experience; functional genomics; genetic variant; genome editing; genome wide association study; genome-wide; human embryonic stem cell; insight; knock-down; model building; mouse genetics; novel; post-doctoral training; predictive modeling; progenitor; programs; rare variant; response; risk prediction; skills; student mentoring; success; symposium; therapeutic candidate; therapeutic development; tool; trait; transcription factor; transcriptome sequencing

PROJECT SUMMARY Accumulating evidence suggests robustness of transcriptional regulation, yet human genetic studies indicate phenotypic sensitivity to transcription factor (TF) dosage in both complex traits and rare disorders, motivating quantitative studies of TF dosage effects. These features are exemplified by the development of the human face, which is frequently disrupted in a range of syndromes with typical features. The aim of this proposal is to develop and apply tools to precisely modulate dosage of craniofacial TFs in cranial neural crest cells, the progenitors of the face, and assess effects across multiple biological levels – molecular, cellular, and morphological. The proposal initially focuses on SOX9, using diverse approaches to understand the rules that determine which regulatory elements and genes are sensitive to SOX9 dosage (Aim 1), as well as their phenotypic consequences (Aim 2). Then, such rules will be generalized to five additional craniofacial TFs (Aim 3) and used to dissect mechanisms underlying genetic variants associated with craniofacial morphology or disease (Aim 4). These studies will reveal drivers of craniofacial morphological and disease variation, provide general insights into transcriptional regulation, and help transform our approach to studying TF function, from binary to quantitative in nature. The proposed research, along with a comprehensive plan for my career development, combines my scientific background and postdoctoral training in functional genomics, gene regulation, and human genetics with opportunities for additional training in machine learning, mouse genetics, and morphological analysis. I will be mentored by Drs. Joanna Wysocka and Jonathan Pritchard in a vibrant scientific environment (Stanford Chemical and Systems Biology) and receive additional training from my advisory committee of Drs. James Ferrell, Anshul Kundaje, and Benedikt Hallgrimsson. My transition to independence will be facilitated by participation in both scientific and non-scientific trainings and workshops, as well as experience in presenting my work at scientific conferences. I will also gain experience mentoring students and technicians, and will hone my grant management and writing skills. Collectively, my mentors have guided over 25 of their former postdocs to independent academic research positions, and they will provide practical advice and feedback during my faculty job search. My long-term career goal is to direct an independent research program aimed at understanding the molecular underpinnings of quantitative variation in craniofacial morphology and disease risk. So far I have achieved significant progress towards this goal through my research experience, publications, and engagement with the broader scientific community. I firmly believe, however, that a K99 mentored phase will maximize my chances for success by providing access to key resources and training that would be otherwise lacking from my postdoctoral experience.

项目摘要 越来越多的证据表明转录调控的稳健性，但人类遗传学研究表明， 在复杂性状和罕见疾病中，表型对转录因子（TF）剂量的敏感性， TF剂量效应的定量研究。这些特点体现在人类的发展上。 面部，这是经常中断的一系列综合征的典型特征。这项建议的目的是 为了开发和应用工具来精确调节颅神经嵴细胞中颅面TF的剂量， 面部的祖细胞，并评估多个生物水平的影响-分子，细胞， 形态学的该提案最初侧重于SOX 9，使用不同的方法来理解规则 确定哪些调控元件和基因对SOX 9剂量敏感（目标1），以及它们的 表型结果（目标2）。然后，这些规则将被推广到另外五个颅面TF (Aim 3）并用于解剖与颅面相关的遗传变异的机制 形态学或疾病（目的4）。这些研究将揭示颅面形态和疾病的驱动因素 变异，提供转录调控的一般见解，并帮助改变我们的方法， 研究TF函数，从二元到定量。 拟议的研究，沿着一个全面的计划，为我的职业发展，结合我的科学 在功能基因组学、基因调控和人类遗传学方面的背景和博士后培训， 机器学习、小鼠遗传学和形态学分析方面的额外培训机会。我会 在充满活力的科学环境中接受乔安娜·威索卡博士和乔纳森·普里查德博士的指导（斯坦福大学 化学和系统生物学），并接受詹姆斯博士的咨询委员会的额外培训。 Ferrell，Anshul Kundaje，and贝内迪克特Hallgrimsson. 通过参加科学和非科学的培训，我向独立的过渡将得到促进 和研讨会，以及在科学会议上介绍我的工作的经验。我也会得到 经验指导学生和技术人员，并将磨练我的赠款管理和写作技巧。 总的来说，我的导师们已经指导了超过25名前博士后进行独立的学术研究 他们将在我的教师求职过程中提供实用的建议和反馈。 我的长期职业目标是指导一个独立的研究项目，旨在了解 颅面形态定量变化和疾病风险的分子基础。到目前为止我已经 通过我的研究经验，出版物， 与更广泛的科学界接触。但是，我坚信，K99指导阶段 我将通过提供关键资源和培训来最大限度地提高我的成功机会， 从我的博士后经验来看，这是我所缺乏的。

项目成果

Precise modulation of transcription factor levels identifies features underlying dosage sensitivity.

• DOI: 10.1038/s41588-023-01366-2
• 发表时间: 2023-05
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Naqvi, Sahin;Kim, Seungsoo;Hoskens, Hanne;Matthews, Harold S. S.;Spritz, Richard A. A.;Klein, Ophir D. D.;Hallgrimsson, Benedikt;Swigut, Tomek;Claes, Peter;Pritchard, Jonathan K. K.;Wysocka, Joanna
• 通讯作者: Wysocka, Joanna