Epidermal differentiation complex

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The epidermal differentiation complex (EDC) is a gene complex comprising over fifty genes encoding proteins involved in the terminal differentiation and cornification of keratinocytes, the primary cell type of the epidermis. In humans, the complex is located on a 1.9 Mbp stretch within chromosome 1q21. [1] [2] The proteins encoded by EDC genes are closely related in terms of function, and evolutionarily they belong to three distinct gene families: the cornified envelope precursor family, the S100 protein family and the S100 fused type protein (SFTP) family. [3]

Contents

It has been hypothesized that the clustering of EDC genes occurred due to duplication events which were evolutionarily favored during the adaptation to terrestrial environments. [3] [4] EDC proteins have been involved in a variety of skin disorders including ichthyosis vulgaris, atopic dermatitis and psoriasis. [5]

History

The epidermal differentiation complex was first described in 1993, [1] and further characterized in 1996, when Dietmar Mischke and colleagues noted the "close functional cooperation among [eleven] structurally and evolutionary related genes". [2] By 2001, 37 genes had been identified as members of the EDC. [6] The number rose to 43 in 2002, [7] and by 2012 a total of 57 genes were considered part of the complex. [3]

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 cornification. CE precursor proteins are cross-linked by transglutaminases. [3] The ratio of CE precursor proteins varies from tissue to tissue. [3] In the epidermis, the most abundant CE component is loricrin (65-70%), while involucrin 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. [3]

Small proline-rich proteins (SPRR proteins)
Late cornified envelope proteins (LCE proteins)

S100 family

The S100 family comprises 17 genes and 6 pseudogenes. S100 proteins contain two EF-hand motifs separated by a hinge region. [3] S100 proteins have various functions and are generally associated with abnormal epidermal differentiation. [3] S100A8 and S100A9 (calgranulin A and B, respectively), dimerize to form calprotectin. Calprotectin, psoriasin (S100A7) and koebnerisin (S100A7A) are antimicrobial peptides. [3]

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. [3] [8] Like S100 proteins, SFTPs contain two calcium-binding EF-hand motifs. [3] These proteins are associated with cytoplasmic intermediate filaments as well as minor components of the CE. [3] Due to their homologous structure they are also known as filaggrin-like proteins. [9] [10]

Regulation of EDC gene expression

EDC genes are transcriptionally controlled by various transcription factors such as krüppel-like factor 4 (KLF4), GATA3, grainyhead-like 3 (GRHL3), aryl hydrocarbon receptor nuclear translocator (ARNT) and NRF2. [3]

Related Research Articles

<span class="mw-page-title-main">Keratinocyte</span> Primary type of cell found in the epidermis

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 of the skin are sometimes referred to as basal keratinocytes. Keratinocytes form a barrier against environmental damage by heat, UV radiation, water loss, pathogenic bacteria, fungi, parasites, and viruses. A number of structural proteins, enzymes, lipids, and antimicrobial peptides contribute to maintain the important barrier function of the skin. Keratinocytes differentiate from epidermal stem cells in the lower part of the epidermis and migrate towards the surface, finally becoming corneocytes and eventually be shed off, which happens every 40 to 56 days in humans.

<span class="mw-page-title-main">S100 protein</span> Family of vertebrate proteins involved in cell division and inflammation

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 encoded by a family of genes whose symbols use the S100 prefix, for example, S100A1, S100A2, S100A3. They are also considered as damage-associated molecular pattern molecules (DAMPs), and knockdown of aryl hydrocarbon receptor downregulates the expression of S100 proteins in THP-1 cells.

<span class="mw-page-title-main">Filaggrin</span>

Filaggrin 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 terminal differentiation of epidermal cells. In humans, profilaggrin is encoded by the FLG gene, which is part of the S100 fused-type protein (SFTP) family within the epidermal differentiation complex on chromosome 1q21.

<span class="mw-page-title-main">Keratinocyte transglutaminase</span> Protein-coding gene in humans

Protein-glutamine gamma-glutamyltransferase K is a transglutaminase enzyme that in humans is encoded by the TGM1 gene.

Corneocytes are terminally differentiated keratinocytes and compose most of the stratum corneum, the outermost layer of the epidermis. They are regularly replaced through desquamation and renewal from lower epidermal layers and are essential for its function as a skin barrier.

Keratohyalin is a protein structure found in cytoplasmic granules of the keratinocytes in the stratum granulosum of the epidermis. Keratohyalin granules (KHG) mainly consist of keratin, profilaggrin, loricrin and trichohyalin proteins which contribute to cornification or keratinization, the process of the formation of epidermal cornified cell envelope. During the keratinocyte differentiation, these granules maturate and expand in size, which leads to the conversion of keratin tonofilaments into a homogenous keratin matrix, an important step in cornification.

<span class="mw-page-title-main">Involucrin</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">S100A11</span> Protein-coding gene in the species Homo sapiens

S100 calcium-binding protein A11 (S100A11) is a protein that in humans is encoded by the S100A11 gene.

<span class="mw-page-title-main">FABP5</span> Protein-coding gene in the species Homo sapiens

Fatty acid-binding protein, epidermal is a protein that in humans is encoded by the FABP5 gene.

<span class="mw-page-title-main">Periplakin</span> Protein-coding gene in the species Homo sapiens

Periplakin is a protein that in humans is encoded by the PPL gene.

<span class="mw-page-title-main">SPRR3</span> Protein-coding gene in the species Homo sapiens

Small proline-rich protein 3 is a protein that in humans is encoded by the SPRR3 gene, which is found within the epidermal differentiation complex (EDC).

<span class="mw-page-title-main">Corneodesmosin</span> Protein-coding gene in the species Homo sapiens

Corneodesmosin is a protein that in humans is encoded by the CDSN gene.

<span class="mw-page-title-main">Envoplakin</span> Protein-coding gene in the species Homo sapiens

Envoplakin is a protein that in humans is encoded by the EVPL gene.

<span class="mw-page-title-main">SPRR1B</span> Protein-coding gene in the species Homo sapiens

Cornifin-B is a protein that in humans is encoded by the SPRR1B gene.

<span class="mw-page-title-main">SPRR1A</span> Protein-coding gene in the species Homo sapiens

Cornifin-A is a protein that in humans is encoded by the SPRR1A gene.

<span class="mw-page-title-main">SCEL (gene)</span> Protein-coding gene in the species Homo sapiens

Sciellin is a protein that in humans is encoded by the SCEL gene.

<span class="mw-page-title-main">S100A7A</span> Protein-coding gene in the species Homo sapiens

Protein S100-A7A (S100A7A), also known as koebnerisin, is a protein that in humans is encoded by the S100A7A gene.

<span class="mw-page-title-main">Trichohyalin</span>

Trichohyalin is a protein that in mammals is encoded by the TCHH gene.

The S100 calcium-binding protein mS100a7a15 is the murine ortholog of human S100A7 (Psoriasin) and human S100A15 (Koebnerisin). mS100a7a15 is also known as S100a15, mS100a7 and mS100a7a and is encoded by the mS100a7a gene

Chromosome 1 open reading frame 68, or C1orf68, is a human gene which encodes for skin-specific protein 32. C1orf68 gene is expressed in the skin, is a part of the epidermal differentiation complex, and potentially plays a role in epidermal cornification, and epidermal barrier function.

References

  1. 1 2 Volz, Armin; Korge, Bernhard P.; Compton, John G.; Ziegler, Andreas; Steinert, Peter M.; Mischke, Dietmar (October 1993). "Physical Mapping of a Functional Cluster of Epidermal Differentiation Genes on Chromosome 1q21". Genomics. 18 (1): 92–99. doi:10.1006/geno.1993.1430. PMID   8276421.
  2. 1 2 Mischke, Dietmar; Korge, Bernhard P.; Marenholz, Ingo; Volz, Armin; Ziegler, Andreas (May 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 (5): 989–992. doi: 10.1111/1523-1747.ep12338501 . PMID   8618063.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 Kypriotou, Magdalini; Huber, Marcel; Hohl, Daniel (September 2012). "The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the 'fused genes' family". Experimental Dermatology. 21 (9): 643–649. doi:10.1111/j.1600-0625.2012.01472.x. PMID   22507538.
  4. ↑ Backendorf, C; Hohl, D (October 1992). "A common origin for cornified envelope proteins?". Nature Genetics. 2 (2): 91. doi:10.1038/ng1092-91. PMID   1303269. S2CID   28646784.
  5. ↑ Hoffjan, S; Stemmler, S (September 2007). "On the role of the epidermal differentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis". British Journal of Dermatology. 157 (3): 441–449. doi:10.1111/j.1365-2133.2007.07999.x. PMID   17573887. S2CID   9434345.
  6. ↑ Marenholz, I; Zirra, M; Fischer, DF; Backendorf, C; Ziegler, A; Mischke, D (March 2001). "Identification of human epidermal differentiation complex (EDC)-encoded genes by subtractive hybridization of entire YACs to a gridded keratinocyte cDNA library". Genome Research. 11 (3): 341–55. doi:10.1101/gr.114801. PMC   311024 . PMID   11230159.
  7. ↑ Elder, James T.; Zhao, Xinping (October 2002). "Evidence for local control of gene expression in the epidermal differentiation complex" (PDF). Experimental Dermatology. 11 (5): 406–412. doi:10.1034/j.1600-0625.2002.110503.x. hdl: 2027.42/71593 . PMID   12366693. S2CID   10189529.
  8. ↑ Wu, Zhihong; Hansmann, Britta; Meyer-Hoffert, Ulf; Gläser, Regine; Schröder, Jens-Michael; Egles, Christophe (22 April 2009). "Molecular Identification and Expression Analysis of Filaggrin-2, a Member of the S100 Fused-Type Protein Family". PLOS ONE. 4 (4): e5227. Bibcode:2009PLoSO...4.5227W. doi: 10.1371/journal.pone.0005227 . PMC   2668185 . PMID   19384417.
  9. ↑ de Guzman Strong, C.; Conlan, S.; Deming, C. B.; Cheng, J.; Sears, K. E.; Segre, J. A. (20 January 2010). "A milieu of regulatory elements in the epidermal differentiation complex syntenic block: implications for atopic dermatitis and psoriasis". Human Molecular Genetics. 19 (8): 1453–1460. doi:10.1093/hmg/ddq019. PMC   2846160 . PMID   20089530.
  10. ↑ Pellerin, Laurence; Henry, Julie; Hsu, Chiung-Yueh; Balica, Stéfana; Jean-Decoster, Catherine; Méchin, Marie-Claire; Hansmann, Britta; Rodriguez, Elke; Weindinger, Stefan; Schmitt, Anne-Marie; Serre, Guy; Paul, Carle; Simon, Michel (April 2013). "Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin". Journal of Allergy and Clinical Immunology. 131 (4): 1094–1102. doi:10.1016/j.jaci.2012.12.1566. PMID   23403047.
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