西湖大学王寿文等研究人员合作开发出基于DNA甲基化表观突变的，高分辨率、非侵入性小鼠和人类单细胞谱系追踪。相关论文于2025年1月16日在线发表在《自然—方法学》杂志上。

研究人员开发了一种基于DNA甲基化上的频繁表观突变的通用谱系追踪工具，并通过研究人员的计算方法MethylTree实现了这一技术。利用已知谱系和表型标签的单细胞全基因组DNA甲基化数据集，MethylTree在不同细胞类型、发育阶段和物种中几乎以100%的准确度重建了谱系历史。

研究人员展示了基于表观突变的单细胞多组学谱系追踪在小鼠和人类血液中的应用，其中MethylTree重现了造血过程中的分化层级。

将MethylTree应用于人类胚胎，研究人员揭示了四细胞阶段的早期命运确立。在小鼠原代血液中，研究人员识别出了约250个造血干细胞克隆。MethylTree为高分辨率、非侵入性和多组学的谱系追踪在人体及其他生物体中的应用开辟了新天地。

据介绍，体内谱系追踪具有极大的潜力，可以揭示组织发育和稳态的基本原则。然而，当前在人类中的谱系追踪依赖于极为罕见的体细胞突变，这限制了其时间分辨率和谱系准确性。

附：英文原文

Title: High-resolution, noninvasive single-cell lineage tracing in mice and humans based on DNA methylation epimutations

Author: Chen, Mengyang, Fu, Ruijiang, Chen, Yiqian, Li, Li, Wang, Shou-Wen

Issue&Volume: 2025-01-16

Abstract: In vivo lineage tracing holds great potential to reveal fundamental principles of tissue development and homeostasis. However, current lineage tracing in humans relies on extremely rare somatic mutations, which has limited temporal resolution and lineage accuracy. Here, we developed a generic lineage-tracing tool based on frequent epimutations on DNA methylation, enabled by our computational method MethylTree. Using single-cell genome-wide DNA methylation datasets with known lineage and phenotypic labels, MethylTree reconstructed lineage histories at nearly 100% accuracy across different cell types, developmental stages, and species. We demonstrated the epimutation-based single-cell multi-omic lineage tracing in mouse and human blood, where MethylTree recapitulated the differentiation hierarchy in hematopoiesis. Applying MethylTree to human embryos, we revealed early fate commitment at the four-cell stage. In native mouse blood, we identified ~250 clones of hematopoietic stem cells. MethylTree opens the door for high-resolution, noninvasive and multi-omic lineage tracing in humans and beyond.

DOI: 10.1038/s41592-024-02567-1

Source: https://www.nature.com/articles/s41592-024-02567-1