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.

项目摘要/摘要 关于细胞状态的详细信息，例如，它的谱系、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。其中包括 修改，DNA甲基化已被广泛研究和剖析组织异质性，疾病 细胞来源，并实施基于液体活检的疾病诊断，这要归功于其化学稳定性和基因组 分布广泛。与大量组织甲基组分析相比，前者会产生复杂的、难以破译的信号 从数千到数百万个细胞，单细胞DNA甲基组图谱在细胞身份相关方面具有优势 申请。尽管近年来单细胞DNA甲基组数据的数量和种类迅速增加 多年来，为其分析提供强大和易于使用的计算工具仍然是一个未得到满足的需求。 关于基于单细胞甲基组数据解释细胞状态的最佳策略尚未达成共识 已到达。我的实验室的长期目标是在人类单细胞水平上阐明表观遗传细胞的身份 老鼠。为了实现这个目标，我提议开发一套计算工具，用于分析单细胞甲基化 数据，包括数据预处理、质量控制、归责、甲基组签名等功能 提取、单元状态注释和探索性可视化。这些软件工具将被设计成 高效、模块化，将设计用于在高性能计算环境和 基本的笔记本电脑。这些工具将能够提醒调查人员潜在的数据质量问题，反馈到 加快甲基化检测的发展，并发现DNA甲基组和 细胞的遗传组成、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 也可用于研究大块组织样本中的细胞群体特征。与这些计算工具一起，我们 还旨在分发一份细胞类型分辨率参考甲基组目录，以造福于研究界。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。这个 要开发的方法可以很容易地插入到更广泛的探索性和翻译应用程序中 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