SMAdd-seq: Probing chromatin accessibility with small molecule DNA intercalation and nanopore sequencing

Area of Science:

• Molecular Biology
• Genomics
• Epigenetics

Background:

• Current methods for mapping chromatin organization rely on large enzymes or single nucleosome resolution.
• These techniques have limitations in providing a comprehensive view of DNA accessibility across the genome.

Purpose of the Study:

• To introduce Add-seq, a novel method for probing genome-wide DNA accessibility.
• To demonstrate the capability of Add-seq in analyzing long DNA molecules and detecting chromatin structure heterogeneity.

Main Methods:

• Developed Add-seq utilizing the small molecule angelicin to selectively modify DNA not bound by nucleosomes.
• Employed Nanopore sequencing to analyze angelicin-modified DNA, capturing long single-molecule reads.
• Utilized a neural network model to detect angelicin modifications from Nanopore current signal data.

Main Results:

• Successfully visualized and analyzed distinct chromatin structures across long DNA molecules using Add-seq.
• Identified expected accessibility patterns around gene loci in *Saccharomyces cerevisiae*.
• Detected heterogeneity in chromatin structure within the yeast population at specific loci.

Conclusions:

• Add-seq provides a high-resolution method for profiling DNA accessibility across long DNA molecules.
• The technique reveals heterogeneity in chromatin organization within cell populations.
• Add-seq offers a valuable new tool for studying genome-wide chromatin structure and dynamics.