A milieu of regulatory elements in the epidermal differentiation complex syntenic block: Implications for atopic dermatitis and psoriasis

Cristina de Guzman Strong, Sean Conlan, Clayton B. Deming, Jun Cheng, Karen E. Sears, Julia A. Segre

Research output: Contribution to journalArticlepeer-review

Abstract

Two common inflammatory skin disorders with impaired barrier, atopic dermatitis (AD) and psoriasis, share distinct genetic linkage to the Epidermal Differentiation Complex (EDC) locus on 1q21. The EDC is comprised of tandemly arrayed gene families encoding proteins involved in skin cell differentiation. Discovery of semidominant mutations in filaggrin (FLG) associated with AD and a copy number variation within the LCE genes associated with psoriasis provide compelling evidence for the role of EDC genes in the pathogenesis of these diseases. To date, little is known about the potentially complex regulatory landscape within the EDC. Here, we report a computational approach to identify conserved non-coding elements (CNEs) in the EDC queried for regulatory function. Coordinate expression of EDC genes during mouse embryonic skin development and a striking degree of synteny and linearity in the EDC locus across a wide range of mammalian (placental and marsupial) genomes suggests an evolutionary conserved regulatory milieu in the EDC. CNEs identified by comparative genomics exhibit dynamic regulatory activity (enhancer or repressor) in differentiating or proliferating conditions. We further demonstrate epidermal-specific, developmental in vivo enhancer activities (DNaseI and transgenic mouse assays) in CNEs, including one within the psoriasis-associated deletion, LCE3C_LCE3B-del. Together, our multidisciplinary study features a network of regulatory elements coordinating developmental EDC gene expression as an unexplored resource for genetic variants in skin diseases. Published by Oxford University Press 2010.

Original languageEnglish (US)
Article numberddq019
Pages (from-to)1453-1460
Number of pages8
JournalHuman molecular genetics
Volume19
Issue number8
DOIs
StatePublished - Jan 20 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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