Epidermal differentiation complex

The "epidermal differentiation complex", also known as EDC for short, is a gene family that is grouped together on chromosome 1 in the 1q21 region. The genes and gene families located there are called EDC genes and are present as clusters (see LCE3A-B-C below). This arrangement is also referred to as a gene complex. In the epidermal differentiation complex, more than fifty 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).

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. EDC proteins are involved in a number of skin diseases, including ichthyosis vulgaris, atopic dermatitis and psoriasis.

Cornified envelope precursor family: The family of cornified envelope precursors comprises genes that code for the proteins that form the so-called cornified envelope. The cornified envelope (CE) is a cross-linked matrix that surrounds terminally differentiated squamous epithelial cells after the keratinization process. The CE precursor proteins are cross-linked by transglutaminases. The ratio of CE precursor proteins varies from tissue to tissue (Kypriotou M et al. 2012). In the epidermis, loricrin (65-70%) is the most abundant CE component, while involucrin is a minor component (<5%). The other CE proteins are classified as small proline-rich (SPRR) proteins, of which a subgroup is the late cornification envelope (LCE) protein group (Kypriotou M et al. 2012). The following protein families are involved in the EDC:

• Cornified envelope precursor family: Involucrin (IVL); Loricrin (LOR); Small proline-rich proteins (SPRR proteins); SPRR1A (Cornifin A); SPRR1B (Cornifin B); SPRR2A; SPRR2B; SPRR2C; SPRR2D; SPRR2E; SPRR2F; SPRR2G; SPRR3; SPRR4
• Late cornified envelope proteins (LCE proteins): LCE1A; LCE1B; LCE1C; LCE1D; LCE1E; LCE1F; LCE2A; LCE2B; LCE2C; LCE2D; LCE3A; LCE3B; LCE3C; LCE3D; LCE3E; LCE41A; LCE5A; LCE6A; C1orf68
• S100 proteins: The S100 family consists of 17 genes and 6 pseudogenes. S100 proteins contain two EF-hand motifs separated by a hinge region. S100 proteins have various functions and are generally associated with abnormal epidermal differentiation. S100A8 and S100A9 (calgranulin A and B, respectively) dimerize and form calprotectin. Calprotectin, psoriasin (S100A7) and coebnerisin (S100A7A) are antimicrobial peptides. Other S100 proteins are: S100A7L2; S100A8 (calgranulin A); S100A9 (calgranulin B); S100A10; S100A11; S100A12 (calgranulin C); S100A13; S100A14; S100A16.
• SFTP family (S100 proteins of the fused type): The family of S100 fusion-type proteins (SFTP) comprises genes that are mainly expressed in stratified epithelia and play a role in epithelial homeostasis. Like the S100 proteins, the SFTPs also contain two calcium-binding EF-hand motifs. Due to their homologous structure, they are also referred to as filaggrin-like proteins: filaggrin (FLG gene); filaggrin-2 (FLG2); trichohyalin (TCHH gene); trichohyalin-like 1 (TCHHL1); cornulin (CRNN); repetin (RPTN); hornerin (HRNR).

The genes of this family fulfill different functions, but together they are involved in a superordinate task, namely the complex differentiation process of the epidermis. The EDC genes encode both interacting structural proteins (see also Cornified envelope) and regulatory proteins of the epidermis.

Such arrangements in the human genome are rather rare. A well-known example of such a gene complex is the complex for the major histocompatibility genes (MHC, major histocompatibility complex) in humans. This gene complex is localized on chromosome 6. More than 50 genes are bundled in the 6p21.3 region, which carry out the complex tasks of the MHCs (presentation of antigens on the cell surface, their processing and introduction into the cell, etc.).

Arrangements such as those for the EDC are rather rare in the human genome.

A well-known example of such a gene complex is the complex for the major histocompatibility genes (MHC, major histocompatibility complex) in humans. This gene complex is localized on chromosome 6. More than 50 genes are bundled in the 6p21.3 region, which carry out the complex tasks of the MHCs (presentation of antigens on the cell surface, their processing and introduction into the cell, etc.).

The activity of the transcription factor NFAT5 in keratinocytes is controlled by osmotic stress. After ablation of NFAT5, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), is significantly increased. This increase was found together with an increase in numerous members of the "epidermal differentiation complex" (EDC) ( Muhammad K et al. 2021)

1. Hoffjan S et al. (2007). On the role of the epidermal differentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis. British Journal of Dermatology 157: 441-449Kypriotou M et al. (2012) The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the 'fused genes' family. Experimental Dermatology 21: 643-649.

2. Mischke D et al. (1996) Genes Encoding Structural Proteins of Epidermal Cornification and S100 Calcium-Binding Proteins Form a Gene Complex ("Epidermal Differentiation Complex") on Human Chromosome 1q21". Journal of Investigative Dermatology 106: 989-992.

3. Muhammad K et al. (2021) NFAT5 Controls the Integrity of Epidermis. Front Immunol 12:780727.

4. Volz A et al. (1993) Physical Mapping of a Functional Cluster of Epidermal Differentiation Genes on Chromosome 1q21. Genomics 18: 92-99.