Cicero Predicts cis-Regulatory DNA Interactions from Single-Cell Chromatin Accessibility Data

Area of Science:

• Genomics
• Molecular Biology
• Epigenetics

Background:

• Connecting regulatory DNA elements to target genes is a significant challenge in genomics.
• Understanding gene regulation requires identifying functional links between distal DNA elements.

Purpose of the Study:

• To introduce Cicero, an algorithm for identifying co-accessible DNA elements and linking them to target genes.
• To investigate the role of dynamically accessible elements in orchestrating gene regulation during myoblast differentiation.

Main Methods:

• Developed the Cicero algorithm to analyze single-cell chromatin accessibility data.
• Applied Cicero to identify co-accessible DNA element pairs and form "chromatin hubs."
• Utilized pseudotemporal analysis to track dynamic changes in DNA elements during differentiation.

Main Results:

• Cicero successfully links regulatory elements to putative target genes.
• Identified "chromatin hubs" characterized by physical proximity, shared transcription factors, and coordinated epigenetic changes.
• Observed that most DNA elements remain stable within chromatin hubs during differentiation.
• Discovered a subset of MYOD1-bound elements exhibit early opening dependent on PBX1 and MEIS1.

Conclusions:

• Cicero provides a powerful strategy for dissecting cis-regulatory architecture and mechanisms.
• The findings illuminate the dynamic orchestration of gene regulation by chromatin hubs in differentiating cells.
• This approach enables genome-wide analysis of regulatory element function and sequence determinants.