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.

项目摘要许多非孟德尔（多基因）人遗传疾病涉及多个因果基因座，在非编码区域基因组，涉及调节元件中的突变，而不是蛋白质编码基因作为原因疾病。解读这些人遗传疾病的病因需要了解基因在发育和稳态期间受到调节，以产生功能性细胞态。该法规已编码通过表观遗传染色质态，并在调节元件的DNA序列中进行遗传编码例如增强剂，启动子，消音器和绝缘子。但是，这些监管要素及其活动人类细胞中的状态与当前技术无法解析。作为异常基因调控可能是基础的许多人类疾病，理解（1）调节性DNA元素的功能以及（2）其活性动态在健康的人类发展过程中至关重要。要解决这两个问题，我建议：（i）开发新的在单个细胞中介绍多模式染色质状态的实验方法；（ii）确定监管的改变元素激活指出在人造血期间选择细胞命运的选择；（iii）识别DNA序列特征对于调节元件功能很重要；（iv）建立社区工具和资源以分析单细胞染色质数据。这些目标共同为审问的方法和资源提供人类功能基因组以及生成人类细胞类型的调节状态动力学的鉴定。为了成功实现这些目标，我将接受联席会员Rahul Satija博士支持的其他培训（单细胞生物学），Vijay Sankaran博士（造血），Danny Reinberg博士（Gene Congulation）和David博士知识（机器学习）。我制定了一项为期5年的职业发展计划，该计划整合了科学培训在造血和基因调节，深度学习，广泛领导方面的实践培训和指导通过课程和指导以及有关学术写作的研讨会和研讨会的培训。我的团队科学导师将在学术求职方面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发展的理想环境，提供了尖端在丰富的跨学科环境中，研究机构和机会进行进一步的职业发展。拟议的研究计划和职业发展计划的完成将启动我的独立科学生涯是单细胞表观基因组学领域的领导者。