The epidermal differentiation complex (EDC) is a

gene complex In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

comprising over fifty genes encoding proteins involved in the terminal differentiation and

cornification Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, hor ...

keratinocytes Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referred ...

, the primary cell type of the

epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...

. In humans, the complex is located on a 1.9 Mbp stretch within

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ar ...

q21. The proteins encoded by EDC genes are closely related in terms of function, and evolutionarily they belong to three distinct

gene families A gene family is a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions. One such family are the genes for human hemoglobin subunits; the ten genes are in two clusters on ...

: the cornified envelope precursor family, the

S100 protein The S100 proteins are a family of low molecular-weight proteins found in vertebrates characterized by two calcium-binding sites that have helix-loop-helix ("EF-hand-type") conformation. At least 21 different S100 proteins are known. They are enc ...

family and the S100 fused type protein (SFTP) family. It has been hypothesized that the clustering of EDC genes occurred due to

duplication Duplication, duplicate, and duplicator may refer to: Biology and genetics * Gene duplication, a process which can result in free mutation * Chromosomal duplication, which can cause Bloom and Rett syndrome * Polyploidy, a phenomenon also known ...

events which were evolutionarily favored during the adaptation to terrestrial environments. EDC proteins have been involved in a variety of skin disorders including

ichthyosis vulgaris Ichthyosis vulgaris (also known as "autosomal dominant ichthyosis" and "Ichthyosis simplex") is a skin disorder causing dry, scaly skin. It is the most common form of ichthyosis,Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medic ...

atopic dermatitis Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin (dermatitis). It results in puritis, itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which often thickens o ...

and

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

History

The epidermal differentiation complex was first described in 1993, and further characterized in 1996, when Dietmar Mischke and colleagues noted the "close functional cooperation among

leven Leven may refer to: People * Leven (name), list of people with the name Nobility * Earl of Leven a title in the Peerage of Scotland Placenames * Leven, Fife Leven ( gd, Inbhir Lìobhann) is a seaside town in Fife, set in the east Central ...

structurally and evolutionary related genes". By 2001, 37 genes had been identified as members of the EDC. The number rose to 43 in 2002, and by 2012 a total of 57 genes were considered part of the complex.

EDC genes

Cornified envelope precursor family

As its name implies, the cornified envelope (CE) precursor family includes genes that encode the proteins forming the CE. The CE is a cross-linked matrix that surrounds terminally differentiated squamous keratinocytes after a process known as

. CE precursor proteins are cross-linked by

transglutaminase Transglutaminases are enzymes that in nature primarily catalyze the formation of an isopeptide bond between γ-carboxamide groups ( -(C=O)NH2 ) of glutamine residue side chains and the ε-amino groups ( -NH2 ) of lysine residue side cha ...

s. The ratio of CE precursor proteins varies from tissue to tissue. In the epidermis, the most abundant CE component is

loricrin Loricrin is a protein that in humans is encoded by the ''LOR'' gene. Function Loricrin is a major protein component of the stratum corneum, cornified cell envelope found in terminally differentiated epidermis (skin), epidermal cells. Loricrin ...

(65-70%), while

involucrin Involucrin is a protein component of human skin and in humans is encoded by the ''IVL'' gene. In binding the protein loricrin, involucrin contributes to the formation of a cell envelope that protects corneocytes in the skin. Gene This gene i ...

is a minor component (<5%). The other CE proteins are classified as small proline-rich (SPRR) proteins, a subset of which is the late cornified envelope (LCE) protein group.

S100 family

The S100 family comprises 17 genes and 6 pseudogenes. S100 proteins contain two

EF-hand The EF hand is a helix–loop–helix structural domain or ''motif'' found in a large family of calcium-binding proteins. The EF-hand motif contains a helix–loop–helix topology, much like the spread thumb and forefinger of the human hand, in ...

motifs separated by a hinge region. S100 proteins have various functions and are generally associated with abnormal epidermal differentiation.

S100A8 S100 calcium-binding protein A8 (S100A8) is a protein that in humans is encoded by the ''S100A8'' gene. It is also known as calgranulin A. The proteins S100A8 and S100A9 form a heterodimer called calprotectin Calprotectin is a complex of the m ...

and

S100A9 S100 calcium-binding protein A9 (S100A9) also known as migration inhibitory factor-related protein 14 (MRP14) or calgranulin B is a protein that in humans is encoded by the ''S100A9'' gene. The proteins S100A8 and S100A9 form a heterodimer calle ...

(calgranulin A and B, respectively), dimerize to form

calprotectin Calprotectin is a complex of the mammalian proteins S100A8 and S100A9. Other names for calprotectin include MRP8-MRP14, calgranulin A and B, cystic fibrosis antigen, L1, 60BB antigen, and 27E10 antigen. The proteins exist as homodimers but preferen ...

. Calprotectin, psoriasin (

S100A7 S100 calcium-binding protein A7 (S100A7), also known as psoriasin, is a protein that in humans is encoded by the ''S100A7'' gene. Function S100A7 is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 prot ...

) and knoeberisin (

S100A15 S100 calcium-binding protein A15 (S100A15), also known as koebnerisin and S100 calcium-binding protein A7A (S100A7A), is a protein that in humans is encoded by the ''S100A7A'' (alias:''S100A15'') gene. S100 proteins are a diverse calcium-bindin ...

) are

antimicrobial peptide Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for an ...

SFTP family

The S100 fused type protein (SFTP) family or fused gene family encompasses genes which are mainly expressed in stratified epithelia and play a role in epithelial homeostasis. Like S100 proteins, SFTPs contain two calcium-binding EF-hand motifs. These proteins are associated with cytoplasmic

intermediate filament Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate ''Branchiostoma''. Intermedia ...

s as well as minor components of the CE. Due to their homologous structure they are also known as filaggrin-like proteins. *

filaggrin Filaggrin (filament aggregating protein) is a filament-associated protein that binds to keratin fibers in epithelial cells. Ten to twelve filaggrin units are post-translationally hydrolyzed from a large profilaggrin precursor protein during termina ...

(FLG) * filaggrin-2 (FLG2) *

trichohyalin Trichohyalin is a protein that in mammals is encoded by the ''TCHH'' gene. Discovery In 1903 the name ''trichohyalin'' was assigned to the granules of the inner root sheath (IRS) of hair follicles discovered by Hans Vörner. In 1986 the name was ...

(TCHH) * trichohyalin-like 1 (TCHHL1) * cornulin (CRNN) *

repetin Repetin is an extracellular matrix protein expressed in the epidermis. In humans it is encoded by the ''RPTN'' gene. Repetin is part of the S100 fused-type protein family and contains an EF hand structural domain. It functions in the cornified cel ...

(RPTN) * hornerin (HRNR)

Regulation of EDC gene expression

EDC genes are transcriptionally controlled by various

transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...

such as krüppel-like factor 4 (KLF4),

GATA3 GATA3 is a transcription factor that in humans is encoded by the ''GATA3'' gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes. The GATA3 transcription ...

, grainyhead-like 3 (GRHL3),

aryl hydrocarbon receptor nuclear translocator The ARNT gene encodes the aryl hydrocarbon receptor nuclear translocator protein that forms a complex with ligand-bound aryl hydrocarbon receptor (AhR), and is required for receptor function. The encoded protein has also been identified as the be ...

(ARNT) and

NRF2 Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regul ...

References

{{reflist, 2 Gene complexes Genes on human chromosome 1 Skin