DNA methylation meets lineage tracing: History, recent progress, and future directions

Area of Science:

• Biotechnology
• Genomics
• Developmental Biology

Background:

• Lineage tracing is crucial for understanding development and disease.
• Current genetic engineering methods for lineage tracing are invasive and difficult for human application.
• Endogenous DNA mutations have low rates, posing technical challenges for human lineage tracing.

Purpose of the Study:

• To review and compare MethylTree and EPI-Clone, novel epimutation-based lineage tracing tools.
• To highlight the advantages of noninvasive epimutation-based lineage tracing in humans.
• To demonstrate MethylTree's compatibility with EPI-Clone data for a unified solution.

Main Methods:

• MethylTree: A computational tool for predicting cell lineages from single-cell DNA methylation data (genome-wide or targeted).
• EPI-Clone: A targeted approach requiring specific CpG panel selection for tissues, validated in blood.
• Comparative analysis of MethylTree and EPI-Clone scalability, cost, resolution, and tissue applicability.

Main Results:

• Epimutations occur at a sufficient rate (0.001 per CpG site per division) for lineage tracing.
• MethylTree provides high-resolution lineage tracing across different tissues.
• EPI-Clone is scalable and cost-effective, particularly for blood.
• MethylTree successfully integrates with EPI-Clone data, offering a unified approach.

Conclusions:

• Epimutation-based lineage tracing offers a high-resolution, noninvasive method for human studies.
• MethylTree and EPI-Clone represent significant advancements in this field.
• Further tool development and consideration of biological applications will expand the utility of epimutation-based lineage tracing.