Epidermal genes of differentiation

Epidermal differentiation genes are genes whose products control the gradual maturation of keratinocytes from the basal layer of the epidermis to the fully keratinized corneocyte. These genes are grouped together as a gene family in the "epidermal differentiation complex", or EDC for short.

The main groups of epidermal differentiation genes can be divided into several classes according to their function:

• A. Keratin genes
• Keratins form the intracellular cytoskeleton of keratinocytes.
• KRT5; KRT14: Early differentiation (basal cells, characteristic of proliferating basal keratinocytes)
• KRT1; KRT10: Suprabasal differentiation (these are to be defined as markers of incipient terminal differentiation)
• KRT2; KRT9/KRT6 A-C/ KRT16/ KRT17: Specialized keratins (KRT2; KRT9/palms/foot soles; KRT6, KRT16, KRT17/genes for stress and wound healing keratins)
• B. Cornified Envelope (CE) - structural proteins(IVL/LOR/Envoplakin/Periplakin/Small proline-rich proteins): These genes encode proteins that form the outer "horn coat". Important representatives are genes that code for involucrin (IVL); loricrin (LOR); envoplakin (EVPL); periplakin (PPL); small proline-rich proteins (SPRR1-SPRR4). Functionally, the encoded proteins serve to build a resistant, cross-linked protein scaffold.
• C. S100 gene family: S-100 genes encode calcium-binding proteins with a regulatory function. Important epidermal representatives of this gene family are: S100A7 (psoriasin); S100A8 / S100A9 (calprotectin); S100A10; S100A11. The functional significance of the proteins encoded by this gene family lies in the modulation of inflammation, in antimicrobial defense and in the control of differentiation.
• D. Filaggrins (FLG)- these genes encode key molecules of epidermal differentiation. Filaggrin (FLG) is the main component of the keratohyalin granules of the upper str. granulosum. It is present as the 400 kDa protein profilaggrin, which is cleaved by proteolytic differentiation into 10-12 filaggrin polypeptides of 37 kDa in a final differentiation step in the str. granulosum. Filaggrin is encoded by the FLG gene, which is localized on chromosome 1q21. Filaggrins are responsible for the formation of natural moisturizing factors (NMF). They are essential for barrier function. > 40 variants are known in this gene. Mutations in the filaggrin gene are associated with atopic dermatitis, among other things. Phenotypically, these patients with early onset of atopic dermatitis, high serum IgE levels and palmar hyperlinearity can be identified as FLG mutation carriers. Associated genes are FLG2. This gene codes for trichohyalin
• E. Lipid and barrier genes (ABCA12/ALOX12B/ ALOXE3): The proteins encoded by these genes are crucial for the formation of the intercellular lipid barrier: The following genes play an important role here: ABCA12 (lipid transporter)-ALOX12B/ ALOXE3 (lipoxygenases)/ELOVL4 (fatty acid elongation)/CERS3 (ceramide synthesis)/PNPLA1. Mutations in these genes lead to severe cornification disorders (e.g. ichthyosis).
• F. Cross-linking enzymes (TGM1/TGM3/ TGM5): Genes of the transglutaminase family are responsible for the stabilization of the cornified envelope, in particular TGM1, TGM3, TGM5. The gene products catalyze the covalent cross-linking of: Involucrin, Loricrin and SPRR proteins
• G. Transcription factors of the differentiation genes (KLF4/ GRHL3,/ OVOL1/2): The genes of this epidermal protein family control the entire program at the regulatory level: TP63 as the master regulator of epidermal development; KLF4, GRHL3, OVOL1/2 and the genes of the NOTCH signaling pathway. Their coding products control cell cycle exit, activation of differentiation genes and layer-specific gene expression.

In the epidermal differentiation complex, >50 genes are now known that code for proteins involved in the terminal differentiation and keratinization of keratinocytes. The proteins encoded by the EDC genes are closely related in their function and, in evolutionary terms, belong to three different gene families:

• the "cornified envelope precursor family"
• the S100 protein family
• the family of S100 fusion proteins (SFTP).

The epidermal differentiation genes mainly encode: structural proteins, cross-linking proteins, lipid metabolism proteins, regulatory transcription factors. It has been hypothesized that the accumulation of EDC genes is due to duplication events that were evolutionarily favored during adaptation to the terrestrial environment.

Structurally, epithelial differentiation involves different processes:

• silencing of proliferation-associated genes
• Activation of differentiation-dependent genes
• Formation of a mechanically stable and water-impermeable horny mantle.

EDC proteins are involved in a number of skin diseases in which disorders of the epidermal differentiation genes play a central role, for example in: Inflammatory dermatoses such as atopic dermatitis and psoriasis as well as keratinization disorders.