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.

项目概要 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对转录因子（TF）剂量的表型敏感性，激励 TF 剂量效应的定量研究可以通过人类的发育来例证。 面部，在一系列具有典型特征的综合症中经常被破坏。该提案的目的是。 开发并应用工具来精确调节颅神经嵴细胞中颅面 TF 的剂量， 面部祖细胞，并评估多个生物水平（分子、细胞和 该提案最初关注 SOX9，使用多种方法来理解规则。 确定哪些调控元件和基因对 SOX9 剂量敏感（目标 1），以及它们的 然后，这些规则将推广到另外五个颅面 TF。 （目标 3）并用于剖析与颅面相关的遗传变异的潜在机制 形态或疾病（目标 4）。这些研究将揭示颅面形态和疾病的驱动因素。 变异，提供对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。 拟议的研究以及我职业发展的全面计划结合了我的科学知识 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 我将有机会接受机器学习、小鼠遗传学和形态分析方面的额外培训。 在充满活力的科学环境中接受乔安娜·威索卡 (Joanna Wysocka) 和乔纳森·普里查德 (Jonathan Pritchard) 博士的指导（斯坦福大学） 化学和系统生物学）并接受詹姆斯博士顾问委员会的额外培训。 费雷尔、安舒尔·昆达杰和贝内迪克特·霍尔格里姆森。 参加科学和非科学培训将有助于我向独立的过渡 和研讨会，以及在科学会议上展示我的工作的经验。 指导学生和技术人员的经验，并将磨练我的赠款管理和写作技巧。 我的导师总共指导了超过 25 名前博士后进行独立学术研究 职位，他们会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 到目前为止，我已经了解了颅面形态定量变化和疾病风险的分子基础。 通过我的研究经验、出版物和 然而，我坚信 K99 指导阶段。 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 否则我的博士后经验就缺乏了。

项目成果

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

转录因子水平的精确调节可识别剂量敏感性的潜在特征。

• 发表时间: 2023-05
• 影响因子: 30.8
• 作者: Naqvi, Sahin;Kim, Seungsoo;Hoskens, Hanne;Matthews, Harold S;Spritz, Richard A;Klein, Ophir D;Hallgrímsson, Benedikt;Swigut, Tomek;Claes, Peter;Pritchard, Jonathan K;Wysocka, Joanna
• 通讯作者: Wysocka, Joanna