Genetic Variations in Non-coding Regulatory Regions in Linear Morphea
Dawn Zhang Eichenfield, MD, PhD, University of California, San Diego, Medical Center, La Jolla, California
Disclosures: This research was funded by the Women’s Dermatologic Society and the Pediatric Dermatology Research Alliance.
Dawn Zhang Eichenfield, MD, PhD
Linear morphea is a chronic inflammatory and pro-fibrotic disease that can be debilitating and disfiguring. It generally presents at an earlier age of onset than other subtypes of morphea. Like other autoimmune diseases, linear morphea presents predominantly in females, has a familial contribution, and has been associated with particular environmental triggers. Beyond this, however, the full pathogenesis of this disease remains unknown. A more thorough understanding of the causes of linear morphea—genetic and environmental—is the first step toward improved diagnosis and treatment.
Lesions of linear morphea predominantly follow Blaschko’s lines, a pattern of lines on the skin thought to represent pathways of epidermal cell migration and proliferation during fetal development. This presentation suggests that genetic mosaicism may be at play, although studies utilizing whole exome sequencing have not found causative somatic genetic mutations in protein-coding regions.1,2 Recent studies, however, have increasingly shown that genetic diseases, including autoimmune disorders, can be caused by mutations in non-protein coding regions. For example, Castellanos-Rubio et al3 recently identified a long non-coding RNA that plays an essential role in the maintenance of intestinal mucosal immune homeostasis and its genetic polymorphisms contribute to inflammation in celiac disease. New sequencing technologies further highlight the complexities of gene regulation. Recent studies of the ENCODE project estimate hundreds of thousands of non-promoter genomic elements that are regulated in a cell-specific and signal-dependent manner through different transcription factors, non-coding RNAs, as well as other transcriptional regulatory elements.4 Taken together, this data suggests that genetic mutations in non-coding regulatory regions have the potential to initiate and perpetuate autoimmune disease.
Our hypothesis is that key somatic genetic mutations in non-coding regulatory regions result in altered transcription factor binding and downstream changes in gene expression, which produce a predisposition to development of linear morphea. To test this hypothesis, we are utilizing whole genome sequencing and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-Seq) on normal and lesional skin in a cohort of patients with linear morphea to identify disease-specific regulatory variants. If initial experiments yield candidate genes or regulatory regions, we will validate these loci through functional assays to identify variants that stimulate a pro-fibrotic response.
Altogether, these studies will help identify new insights into key genetic contributions to the pathogenesis and transcriptional regulation of linear morphea. Understanding the molecular and genetic basis of linear morphea is significant as it is the first step toward improved pharmacological treatments and preventive strategies for linear morphea.
References
- Higgins R, Smith A, Walchli R, et al. Absence of somatic mutations in linear localized scleroderma. J Investig Dermatol. 2017;137:S271.
- Higgins R, Theiler M, Smith A, et al. Genetic architecture of linear localized scleroderma. J Investig Dermatol. 2018;138:S138.
- Castellanos-Rubio A, Fernandez-Jimenez N, Kratchmarov R, et al. A long noncoding RNA associated with susceptibility to celiac disease. Science. 2016;352:91-95.
- Hoffman MM, Ernst J, Wilder SP, et al. Integrative annotation of chromatin elements from ENCODE data. Nucleic Acids Res. 2013;41:827-841.
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