# Sporiasis Pathogenesis and Treatment
## 2 Pathogenesis
### Epigenetics  
The quest for the missing heritability associated with psoriasis candidate genes has fueled the search for epigenetic modifications. Epigenetic mechanisms modify gene expression without changing the genomic sequence; some examples include: long noncoding RNA (lncRNA), microRNA (miRNA) silencing, and cytosine and guanine (CpG) methylation.  
lncRNA are at least 200 nucleotides long, and are not transcribed to protein. At least 971 lncRNAs have been found to be differentially expressed in psoriatic plaques compared to normal skin [126; 127; 128; 129; 130; 131]. Thereof, three differentially expressed lncRNAs in proximity to known psoriasis susceptibility loci at _CARD14_, _LCE3B/LCE3C_, and _IL-23R_, and are thought to modulate their function [127].  
miRNAs are small, evolutionarily conserved, noncoding RNAs that base pair with complementary sequences within mRNA molecules, and regulate gene expression at the posttranscriptional level, usually downregulating expression. Most of the studies of miRNAs in association with psoriasis address the plaque-type variant (see Table 1), and so far, more than 250 miRNAs are aberrantly expressed in psoriatic skin [132; 133; 134; 135]. A prominent role has been attributed to miR-31, which is upregulated in psoriatic skin and regulates NF-kB signaling as well as the leukocyte-attracting and endothelial cell-activating signals produced by keratinocytes [135]. miR-21 is an oncomiR with a role in inflammation, and has been found to be elevated in psoriatic skin. Increased miR-21 has been localized not only to the epidermis, but is also found in the dermal inflammatory infiltrates, and correlates with elevated TNF-\(\alpha\) mRNA expression [136]. miR-221 and miR-222 are among other upregulated miRNAs in psoriatic skin [132]. The aberrant expression of miR-21, miR-221, and miR-222 correlates with a downregulation of the tissue inhibitor of metalloprotease 3 (TIMP3) [137; 138]. TIMP3 is a member of the matrix metalloproteinase family with a wide range of functions. Increased levels of said miRs are thought to result in unopposed matrix metalloproteinase activity, leading to inflammation (partly via TNF-\(\alpha\)-mediated signaling) and epidermal proliferation [138]. miR-210 was found to be highly expressed in psoriasis patients, and induced Th17 and Th1 differentiation while inhibiting Th2 differentiation through STAT6 and LYN repression [139].  
Serum levels of miR-33, miR-126, and miR-143, among others, have been proposed as potential biomarkers of disease [140; 141]. However, the studies have so far failed to consistently present elevations of a single miRNA in psoriatic patients. Thus, alterations of miRNA expression are better interpreted in the context of miRNA profiles, which have been reported to shift following psoriasis treatments [132]. Thus, miRNA expression profiles could potentially be used to predict response to treatment and personalize therapies.  
DNA methylation is another epigenetic mechanism that can alter gene expression in a transient or heritable fashion, and primarily involves the covalent modification of cytosine and guanine (CpG) sequences. CpG methylation is usually repressive unless it inhibits transcriptional repressors, in which case it results in gene activation. Around 1100 differentially methylated CpG sites were detected between psoriatic and control skin. Of these sites, 12 corresponded to genes regulating epidermal differentiation, and were upregulated due to a lower methylation pattern. Said changes in DNA methylation reverted to baseline under anti-TNF-\(\alpha\) treatment, indicating that CpG methylation in psoriasis is dynamic [148; 149]. Further research will shed light on the functional relevance of epigenetic regulation in psoriasis.