Dynamic Chromatin Architecture of the Epidermal Differentiation Complex (EDC)

Abstract

Transcription is a tightly regulated process that enables genomic loci to be expressed in a tissue‐specific manner. The molecular mechanisms of transcriptional regulation are complex and multimodal, from enzymatic epigenetic modifications associated with either repressed or active chromatin at specific loci to physical enhancer–promoter contacts conducive to gene expression, and the nonrandom positioning of the chromatin within the nucleus. The skin epidermis provides an accessible model to investigate tissue‐specific expression and differentiation. Central to keratinocyte differentiation is the transcriptional activation of many genes encoded by the Epidermal Differentiation Complex (EDC). The past decade has witnessed pivotal discoveries for deoxyribonucleic acid (DNA) methylation and histone methylation and acetylation in the regulation of the EDC and epidermal differentiation. Moreover, chromatin conformation capture studies have revealed the importance of dynamic chromatin remodelling at the EDC upon epidermal differentiation. The studies, modelled on the EDC and described herein, have revolutionised our understanding of tissue‐specific expression.

Key Concepts

  • Tissue‐specific transcription is tightly regulated and complex.
  • Epidermal differentiation and the regulation of the EDC locus provide an accessible model towards understanding the molecular mechanisms of tissue‐specific transcriptional regulation.
  • Distinct epigenetic patterns of DNA methylation and histone modifications contribute to locus‐specific expression at a genome‐wide level.
  • Histone methyltransferases JMJD3, EZH2 and SETD8 and histone deacetylase HDAC1/2 modify the chromatin of the EDC to permit proper epidermal development.
  • The EDC preferentially migrates towards the interior of the nucleus for active transcription.
  • Enhancers are regulatory elements whose proximal interactions with gene promoters drive tissue‐specific expression.
  • Epidermal enhancer–promoter interactions are dynamic between proliferative and differentiated keratinocytes with a second class of interactions stable between developmental states.
  • The capturing of cell type‐specific chromatin states identifies topologically associated domains (TADs) comprised of enriched physical chromatin contacts that include enhancer–promoter interactions.
  • The EDC is spatially organised into four TADs.

Keywords: epidermal differentiation complex; transcription; chromatin; epigenetics; enhancer; histone; methylation; skin; epidermis

Figure 1. Schematic of the epidermal differentiation complex. (a) Human EDC Hg38. Protein coding genes in black, long non‐coding RNAs in green. (b) Mouse EDC, mm10. Transcript coordinates for human obtained from Ensembl 90, mouse obtained from Ensembl 91. When multiple isoforms are reported, the longest isoform is displayed here.
Figure 2. Schematic of chromatin regulation.
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Mathyer, Mary Elizabeth, and de Guzman Strong, Cristina(Sep 2018) Dynamic Chromatin Architecture of the Epidermal Differentiation Complex (EDC). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027960]