Accurate and robust 3D genome feature discovery from multiplexed DNA FISH

Area of Science:

• Genomics
• Molecular Biology
• Biophysics

Background:

• Multiplexed DNA FISH (FISH Omics) offers high-resolution 3D genome mapping in thousands of cells.
• Existing computational methods, adapted from Hi-C, do not account for axis-specific measurement errors in FISH data.
• Accurate identification of 3D genome features like compartments, TADs, and loops is crucial for understanding genome regulation.

Purpose of the Study:

• To develop a novel computational framework, ArcFISH, for accurate and robust 3D genome analysis from multiplexed DNA FISH data.
• To explicitly model and correct for axis-specific measurement errors inherent in FISH imaging.
• To enable reliable detection of multi-level 3D genome structures at kilobase resolution.

Main Methods:

• ArcFISH employs a unified statistical framework to model axis-specific measurement errors.
• The method was evaluated using simulated and experimental multiplexed DNA FISH datasets.
• ArcFISH analyzes chromatin loops, TAD boundaries, and A/B compartments.

Main Results:

• ArcFISH reliably identifies chromatin loops even with heterogeneous measurement errors.
• Detected TAD boundaries are highly enriched for active histone marks (H3K4me3, H3K36me3).
• Accurate A/B compartment assignment requires as few as 30 chromatin traces.

Conclusions:

• ArcFISH provides a robust computational solution for analyzing 3D genome organization from FISH Omics data.
• The method reveals cell-type-specific chromatin loops and TADs in mouse embryonic stem cells and neurons.
• ArcFISH facilitates a deeper understanding of genome structure-function relationships.