The dynamic, combinatorial cis-regulatory lexicon of epidermal differentiation

Area of Science:

• Genomics
• Molecular Biology
• Developmental Biology

Background:

• Transcription factors bind DNA motifs in cis-regulatory elements (CREs) to control gene expression during cell transitions.
• Understanding the combinatorial nature of CREs and their motif lexicons in dynamic gene regulation remains challenging.

Purpose of the Study:

• To quantitatively model the cis-regulatory logic of chromatin accessibility during epidermal differentiation.
• To identify cooperative DNA sequence rules governing dynamic gene expression modules in skin development.

Main Methods:

• Multiomic data profiling of chromatin and gene expression dynamics during epidermal differentiation.
• Application of an interpretable deep-learning framework to model cis-regulatory sequences.
• Validation using massively parallel reporter assays.

Main Results:

• Identified 40,103 dynamic CREs linked to 3,609 dynamically expressed genes.
• Discovered cooperative DNA sequence rules in dynamic CREs that regulate synchronous gene modules.
• Enrichment of human polygenic skin disease variants within these time-dependent combinatorial motif rules.

Conclusions:

• The study elucidates the combinatorial cis-regulatory lexicon of epidermal differentiation.
• Presents a general framework for deciphering the organizational principles of the cis-regulatory code in dynamic gene regulation.
• Highlights the role of combinatorial motif rules in skin development and disease susceptibility.