Decoding Single-cell DNA Methylomes for Epigenetic Cell Identity

解码单细胞 DNA 甲基化组以了解表观遗传细胞身份

• 批准号: 10703425
• 负责人: Wanding Zhou
• 金额: $ 44.5万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703425
• 关键词: Acceleration; Biological; Biological Assay; Catalogs; Cell Cycle Stage; Cell Lineage; Cells; Chromatin; Communities; Competence; Computing Methodologies; Consensus; DNA; DNA Methylation; DNA Modification Process; Data; Developmental Biology; Disease; Engineering; Environment; Epigenetic Process; Eukaryota; Feedback; Genetic Transcription; Goals; Heterogeneity; High Performance Computing; Human; Link; Machine Learning; Methods; Methylation; Mitotic; Modification; Mus; Quality Control; Recording of previous events; Research; Research Personnel; Resolution; Role; Signal Transduction; Software Tools; Techniques; Tissue Sample; Tissues; Transcriptional Regulation; Visualization; Work; assay development; cell population study; cell type; chemical stability; computational suite; computerized tools; data quality; design; disease diagnosis; genetic makeup; genome-wide; human disease; laptop; liquid biopsy; methylome; multiple omics; proliferation potential; tool; trait; translational applications

PROJECT SUMMARY / ABSTRACT Detailed information about the state of a cell, e.g., its lineage, mitotic history, proliferation potential, and functional competence, consolidates through epigenetic modifications of its DNA and chromatin. Among these modifications, DNA methylation has been widely studied and profiled to dissect tissue heterogeneity, disease cell of origin, and implement liquid biopsy-based disease diagnosis, thanks to its chemical stability and genome- wide distribution. Compared to bulk tissue methylome assays, which yield convoluted, hard-to-decipher signals from thousands to millions of cells, single-cell DNA methylome profiling is advantageous in cell identity-related applications. Despite the rapid increase in the volume and variety of single-cell DNA methylome data in recent years, availability of powerful and easy-to-use computational tools for their analyses is still an unmet demand. Consensus on the optimal strategy of interpreting cell states based on single-cell methylome data has not been reached. My lab’s long-term goal is to elucidate epigenetic cell identities at the single-cell level in humans and mice. Towards that goal, I propose to develop a suite of computational tools, for analyzing single-cell methylation data, that will encompass functions for data preprocessing, quality control, imputation, methylome signature extraction, cell state annotation, and exploratory visualization. These software tools will be engineered to be efficient, modular, and will be designed to operate both in high-performance computing environments and on basic laptops. These tools would be able to alert the investigator of potential data quality issues, feedback to accelerate methylation assay development, and discover biological links between the DNA methylome and the cell’s genetic makeup, mitotic history, cell-cycle stage, differentiation capacity, and functional state. They can also be used to study cell population traits in bulk tissue samples. Together with these computational tools, we also aim to distribute a cell-type-resolution reference methylome catalog to benefit the research community. My proposed work will deliver computational tools and methylation references to deepen our understanding of the role of DNA methylation in determining cell lineages and provide practical tools for epigenetic cell typing. The methods to be developed could be readily plugged into exploratory and translational applications in broader biomedical contexts.

项目概要/摘要 有关细胞状态的详细信息，例如其谱系、有丝分裂历史、增殖潜力和功能 能力，通过其 DNA 和染色质的表观遗传修饰来巩固。其中 DNA 甲基化已被广泛研究和分析，以剖析组织异质性、疾病 凭借其化学稳定性和基因组，实现基于液体活检的疾病诊断 分布广泛。与大量组织甲基化检测相比，后者会产生复杂、难以解读的信号 从数千到数百万个细胞，单细胞 DNA 甲基化分析在细胞身份相关方面具有优势 应用程序。尽管近年来单细胞 DNA 甲基化数据的数量和种类迅速增加 多年来，用于分析的强大且易于使用的计算工具的可用性仍然是一个未满足的需求。 基于单细胞甲基化组数据解释细胞状态的最佳策略尚未达成共识 达到了。我实验室的长期目标是阐明人类单细胞水平的表观遗传细胞身份 老鼠。为了实现这一目标，我建议开发一套计算工具，用于分析单细胞甲基化 数据，将包含数据预处理、质量控制、插补、甲基化组签名等功能 提取、细胞状态注释和探索性可视化。这些软件工具将被设计为 高效、模块化，并且将被设计为在高性能计算环境和 基本笔记本电脑。这些工具将能够提醒调查人员潜在的数据质量问题，反馈给 加速甲基化检测的发展，并发现 DNA 甲基化组和 DNA 之间的生物学联系 细胞的基因组成、有丝分裂历史、细胞周期阶段、分化能力和功能状态。他们可以 也可用于研究大量组织样本中的细胞群特征。与这些计算工具一起，我们 还旨在分发细胞类型分辨率参考甲基化组目录以使研究界受益。我的 拟议的工作将提供计算工具和甲基化参考，以加深我们对 DNA甲基化在确定细胞谱系中的作用，并为表观遗传细胞分型提供实用工具。这 待开发的方法可以很容易地融入更广泛的探索性和转化性应用中 生物医学背景。

项目成果

Comparative epigenome analysis using Infinium DNA methylation BeadChips.

使用 Infinium DNA 甲基化 BeadChip 进行比较表观基因组分析。

• DOI: 10.1093/bib/bbac617
• 发表时间: 2023
• 期刊: Briefings in bioinformatics
• 影响因子: 9.5
• 作者: Ding,Wubin;Kaur,Diljeet;Horvath,Steve;Zhou,Wanding
• 通讯作者: Zhou,Wanding

Comprehensive Evaluation of The Infinium Human MethylationEPIC v2 BeadChip.

Infinium 人类甲基化EPIC v2 BeadChip 的综合评估。

• DOI: 10.1186/s43682-023-00021-5
• 发表时间: 2023
• 期刊: Epigenetics communications
• 作者: Kaur,Diljeet;Lee,SolMoe;Goldberg,David;Spix,NathanJ;Hinoue,Toshinori;Li,Hong-Tao;Dwaraka,VarunB;Smith,Ryan;Shen,Hui;Liang,Gangning;Renke,Nicole;Laird,PeterW;Zhou,Wanding
• 通讯作者: Zhou,Wanding