ESDR SkinChronicles, No. 7, June 2025, by Yaarob Altalli, MSc
“Architectural Rewiring of the 3D Genome During Epidermal Differentiation”
The mammalian nucleus condenses ~2 meter of DNA into a ~10 micrometre sphere, balancing extreme compaction with local accessibility for transcription and replication. This is achieved through hierarchical folding of the 3D genome maintained by several molecular machines. I selected this study because it focuses on how epidermal cells reorganize their 3D genome, accessibility landscape, and enhancer wiring to orchestrate differentiation. By separating basal and suprabasal (including spinus and granular) cells in vivo and applying high-resolution Hi-C, ATAC-Seq, and ChIP-Seq, the Nayak et al., uncover suprabasal-specific loops, enhanced topologically associated domains (TAD) insulation, and an increase in intrachromosomal contacts at the evolutionary conserved epidermal differentiation complex (EDC). The enrichment of H3K27ac and Dlx3 identifies super-enhancers driving key cornification genes, with Dlx3 and Klf4 forming a combinatorial hub that scaffolds long-range promoter–enhancer interactions. This comprehensive multi-omics atlas reveals that differentiation entails not just gene activation but a rewiring of chromatin architecture, selective chromatin opening at enhancers, and targeted promoter–enhancer contacts. The study’s integration of spatial genomics and transcriptional control provides a good insight on how higher-order chromatin architecture governs lineage specification in epithelial tissues.
Importance to the field and my work:
The study by Nayak et al. (2023) represents a significant advancement in skin research by providing a comprehensive multi-omics atlas that elucidates the dynamic chromatin landscape during murine epidermal differentiation. This atlas integrates RNA-Seq, ATAC-Seq, Hi-C, and ChIP-Seq data to map gene expression, chromatin accessibility, three-dimensional genome architecture, and histone modifications in basal and suprabasal keratinocytes.
The study offers a foundational framework for understanding the interplay between chromatin architecture and gene regulation in skin differentiation, which is the field I am currently working on. This study offers a valuable reference map to guide my investigation on how epigenetics influence lineage-specific gene expression in skin
