Comprehensive mapping of multimodal chromatin state in single cells

单细胞多模式染色质状态的综合绘图

基本信息

批准号：
10323270
负责人：
Tim Stuart
金额：
$ 11.56万
依托单位：
NEW YORK GENOME CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323270
关键词：
Address Biological Assay Blood Categories Cells Cellular Assay Cellular biology Chromatin Code Communities Computing Methodologies DNA DNA Sequence DNA Sequence Alteration DNA-Binding Proteins Data Data Analyses Data Set Development Development Plans Developmental Process Disease Educational workshop Elements Enhancers Environment Epigenetic Process Etiology Future Gene Expression Gene Expression Regulation Genes Genetic Genetic Diseases Genetic Enhancer Element Genetic Fingerprintings Genetic Transcription Genome Genomics Goals Hematopoiesis Hematopoietic Histones Homeostasis Human Human Development Human Genetics Human Genome Joints Leadership Link Machine Learning Maps Measurement Measures Mentors Mentorship Methods Modeling Mutation New York Occupations Pattern Polycomb Post-Translational Protein Processing Probability Program Development Promoter Regions Proteins RNA Polymerase II Regulation Regulatory Element Research Research Personnel Resolution Resources Signal Transduction Specificity Technology Training Training Support Untranslated RNA Writing base career career development causal variant cell fate specification cell type collaborative environment computing resources convolutional neural network deep learning epigenomics genetic variant histone modification human disease human tissue in silico multimodality promoter reconstruction research facility single cell analysis single-cell RNA sequencing tool trait

项目摘要

PROJECT SUMMARY Many non-Mendelian (polygenic) human genetic diseases involve multiple causal loci in noncoding regions of the genome, implicating mutations in regulatory elements rather than protein-coding genes as the cause of these diseases. Deciphering the etiology of these human genetic diseases requires an understanding of how genes are regulated during development and homeostasis to produce functional cell states. This regulation is encoded both through epigenetic chromatin state, and genetically encoded in the DNA sequence of regulatory elements such as enhancers, promoters, silencers, and insulators. However, these regulatory elements and their activity states in human cells are not resolvable with current technologies. As aberrant gene regulation likely underlies many human diseases, understanding (1) the function of regulatory DNA elements and (2) their activity dynamics during healthy human development are essential. To address these two problems, I propose to: (i) develop new experimental methods to profile multimodal chromatin state in single cells; (ii) identify alterations in regulatory element activation states that guide cell fate choice during human hematopoiesis; (iii) identify the DNA sequence features important for regulatory element function; (iv) build community tools and resources for the analysis of single-cell chromatin data. Together these aims will provide methods and resources for the interrogation of the human functional genome, and the identification of regulatory state dynamics that generate human cell types. To succeed in achieving these aims, I will pursue additional training supported by co-mentors Dr. Rahul Satija (single-cell biology), Dr. Vijay Sankaran (hematopoiesis), Dr. Danny Reinberg (gene regulation), and Dr. David Knowles (machine learning). I have developed a 5-year career development plan that integrates scientific training in hematopoiesis and gene regulation, practical training and mentorship in deep learning, extensive leadership training through courses and mentorship, and seminars and workshops on academic writing. My team of scientific mentors will provide further guidance and mentorship in academic job searches. The New York Genome Center is an ideal environment for research and further career development, providing the cutting-edge research facilities and opportunities for further career development in a rich interdisciplinary environment. Completion of the proposed research program and career development plan will launch my independent scientific career as a leader in the field of single-cell epigenomics.

项目概要许多非孟德尔（多基因）人类遗传病涉及非编码区域的多个致病基因座。基因组，暗示调节元件的突变而不是蛋白质编码基因是这些的原因疾病。破译这些人类遗传疾病的病因需要了解基因如何在发育和稳态过程中受到调节以产生功能性细胞状态。该规定已编码既通过表观遗传染色质状态，又通过基因编码的调控元件 DNA 序列例如增强子、启动子、消音子和绝缘子。然而，这些监管要素及其活动目前的技术无法解析人类细胞的状态。异常的基因调控可能是其基础许多人类疾病，了解 (1) 调控 DNA 元件的功能和 (2) 它们的活动动态在人类健康发展过程中至关重要。针对这两个问题，我建议：（i）开发新的分析单细胞中多模式染色质状态的实验方法； (ii) 确定监管方面的变化人类造血过程中指导细胞命运选择的元素激活状态； (iii) 鉴定DNA序列对调节元件功能重要的特征； (iv) 建立社区工具和资源来分析单细胞染色质数据。这些目标共同将为审讯嫌疑人提供方法和资源。人类功能基因组，以及生成人类细胞类型的调节状态动态的识别。为了成功实现这些目标，我将在共同导师 Rahul Satija 博士的支持下接受额外的培训（单细胞生物学）、Vijay Sankaran 博士（造血）、Danny Reinberg 博士（基因调控）和 David 博士诺尔斯（机器学习）。我制定了融合科学培训的5年职业发展计划造血和基因调控、深度学习实践培训和指导、广泛的领导力通过课程和指导以及学术写作研讨会和讲习班进行培训。我的团队科学导师将为学术求职提供进一步的指导和指导。纽约基因组中心是研究和进一步职业发展的理想环境，提供尖端的研究设施和在丰富的跨学科环境中进一步职业发展的机会。完成拟议的研究计划和职业发展计划将启动我的独立研究作为单细胞表观基因组学领域的领导者的科学生涯。