From Spatial Epigenomes to Clinical Diagnostics: Integrative Methylomics Across Scales and Modalities.

Area of Science:

• Genomics and Epigenetics
• Computational Biology
• Translational Medicine

Background:

• Methylomics is crucial for understanding gene regulation in development and disease.
• Technological and computational advances have rapidly expanded the field.
• A comprehensive synthesis of current methylomics knowledge is needed.

Purpose of the Study:

• To systematically review advances in the methylomics pipeline, from data generation to clinical translation.
• To examine multi-omics integration methods and novel profiling technologies.
• To survey methylation dysregulation in major disease domains.

Main Methods:

• Systematic literature review of methylomics technologies and applications.
• Analysis of large-scale consortium datasets and benchmarking studies.
• Inclusion of single-cell, spatial, long-read sequencing, and cfDNA liquid biopsy approaches.

Main Results:

• Multi-omics integration, particularly with transcriptomics and chromatin accessibility, improves disease mechanism resolution.
• Cell-free DNA (cfDNA) methylation profiling shows promise as a non-invasive, cross-disease monitoring platform.
• Technological barriers are decreasing, but standardization and diversity remain challenges.

Conclusions:

• Methylomics offers significant potential for precision medicine, especially through integrated and liquid biopsy approaches.
• Standardization of analytical workflows and diverse reference datasets are critical for clinical translation.
• Addressing regulatory alignment is key to making methylomics advances broadly accessible.