Genomic, Epigenomic, Transcriptomic, Proteomic and Metabolomic Approaches in Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a high prevalence in the developed countries. It is associated with atopic and non-atopic diseases, and its close correlation with atopic comorbidities has been genetically demonstrated. One of the main roles of genetic studies is to comprehend the defects of the cutaneous barrier due to filaggrin deficit and epidermal spongiosis. Recently, epigenetic studies started to analyze the influence of the environmental factors on gene expression. The epigenome is considered to be a superior second code that controls the genome, which includes alterations of the chromatin. The epigenetic changes do not alter the genetic code, however, changes in the chromatin structure could activate or inhibit the transcription process of certain genes and consequently, the translation process of the new mRNA into a polypeptide chain. In-depth analysis of the transcriptomic, metabolomic and proteomic studies allow to unravel detailed mechanisms that cause AD. The extracellular space and lipid metabolism are associated with AD that is independent of the filaggrin expression. On the other hand, around 45 proteins are considered as the principal components in the atopic skin. Moreover, genetic studies based on the disrupted cutaneous barrier can lead to the development of new treatments targeting the cutaneous barrier or cutaneous inflammation. Unfortunately, at present, there are no target therapies that focus on the epigenetic process of AD. However, in the future, miR-143 could be an important objective for new therapies, as it targets the miR-335:SOX axis, thereby restoring the miR-335 expression, and repairing the cutaneous barrier defects.

Multi-Omics Approach to Improved Diagnosis and Treatment of Atopic Dermatitis and Psoriasis

“…Progress in research has led to the identification of more than 70 genes associated with AD; they can be classified into five groups: genes leading to cutaneous barrier dysfunction, genes associated with altered innate responses, genes associated with acquired immune responses, genes associated with stress responses of the keratinocytes, and genes involved in the metabolism of vitamin D [57,58], as detailed in Table 1. One of the most well-known genes linked to both disease susceptibility and disease severity is FLG, the gene encoding for filaggrin, the main protein responsible for the maintenance of cutaneous epithelium integrity [58].…”

“…Apart from FLG, two other key genes have been identified: OLOV1 (Ovo Like Transcriptional Repressor 1) and IL-13. The former is a transcriptional factor that regulates filaggrin expression [60]; the latter mediates Th2 cell responses [57,58], which predominate in AD. The expression of cutaneous barrier proteins such as filaggrin, loricrin, involucrin, cell adhesion proteins, desmosine, and claudins is decreased by Th2 responses with secretion of IL-4 and IL-13 [57,58].…”

“…The former is a transcriptional factor that regulates filaggrin expression [60]; the latter mediates Th2 cell responses [57,58], which predominate in AD. The expression of cutaneous barrier proteins such as filaggrin, loricrin, involucrin, cell adhesion proteins, desmosine, and claudins is decreased by Th2 responses with secretion of IL-4 and IL-13 [57,58]. Additionally, Th2 responses disrupt the homeostasis of other epithelia, which results in an unbalanced immune response that is ultimately linked to systemic inflammation, airway hyperresponsiveness, and food allergies [57,[74][75][76].…”

“…The expression of cutaneous barrier proteins such as filaggrin, loricrin, involucrin, cell adhesion proteins, desmosine, and claudins is decreased by Th2 responses with secretion of IL-4 and IL-13 [57,58]. Additionally, Th2 responses disrupt the homeostasis of other epithelia, which results in an unbalanced immune response that is ultimately linked to systemic inflammation, airway hyperresponsiveness, and food allergies [57,[74][75][76]. IL-4 gene polymorphisms have also been related to an increased susceptibility to AD [66].…”

Looking into the Skin in Health and Disease: From Microscopy Imaging Techniques to Molecular Analysis

“…Stratum corneum plays a fundamental role in the barrier function of the skin, which depends critically on its molecular architecture [ 1 , 87 , 88 , 89 , 90 ]. For example, significant alterations in the structure of the stratum corneum and in its lipid composition were identified in skin conditions with an impaired barrier function, such as atopic dermatitis [ 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 ].…”