Biological significance of genome-wide DNA methylation profiles in keloids

Lamont R Jones; Joshua Greene; Kang Mei Chen; George Divine; Dhananjay Chitale; Veena Shah; Indrani Datta; Maria J Worsham

doi:10.1002/lary.26063

Biological significance of genome-wide DNA methylation profiles in keloids

Laryngoscope. 2017 Jan;127(1):70-78. doi: 10.1002/lary.26063. Epub 2016 Jun 16.

Authors

Lamont R Jones¹, Joshua Greene¹, Kang Mei Chen¹, George Divine², Dhananjay Chitale³, Veena Shah³, Indrani Datta⁴, Maria J Worsham¹

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Henry Ford Hospital, Detroit, Michigan, U.S.A.
² Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan, U.S.A.
³ Department of Pathology, Henry Ford Health System, Detroit, Michigan, U.S.A.
⁴ Department of Public Health Sciences Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan, U.S.A.

PMID: 27312686
DOI: 10.1002/lary.26063

Abstract

Objectives/hypothesis: To obtain biological insight into keloid pathogenesis and treatment using pathway analysis of genome-wide differentially methylated gene profiles between keloid and normal skin.

Study design: Prospective cohort.

Methods: Genome-wide profiling was previously done, with institutional review board approval, on six fresh keloid and six fresh normal skin tissue samples, using the Infinium HumanMethylation450 BeadChip kit. Statistically significant differentially methylated cytosine-phosphodiester bond-guanines (CpGs, n = 197) between keloid and normal tissue mapped to 152 genes. These genes were uploaded into Ingenuity Pathway Analysis (IPA) software to identify biological functions or regulatory networks interacting. The pathways (or "network") with an enrichment probability value ≤ .01 were subjected to a heuristic filter of keywords associated with keloid pathogenesis.

Results: Of the 197 CpGs, 191 were found in the IPA database and mapped to 152 unique genes. The top 10 hypermethylated genes were ACTR3C, LRRC61, PAQR4, C1orf109, SLCO2B1, CMKLR1, AHDC1, FYCO1, CCDC34, and CACNB2. The top 10 hypomethylated genes were GALNT3, SCML4, PPP1R13L, ANKRD11, WIPF1, MX2, IFFO1, DENND1C, CFH, and GHDC. IPA identified nine pathways with enrichment probability values ≤ .01, of which five (histidine degradation V1, phospholipase C signaling, colorectal cancer metastasis signaling, P2Y purinergic receptor signaling, and Gαi signaling) were associated with keloid keywords and contained "keloid genes" (P < .05).

Conclusions: Genes differentially methylated between keloid and normal skin reside in known bionetwork pathways involved in critical biological functioning and signaling events in the cell. This information could be used to refine screening processes for biological significance to better understand keloid pathogenesis and to develop molecular-targeted therapy.

Level of evidence: NA Laryngoscope, 127:70-78, 2017.

Keywords: Methylation; epigenetics; keloid; pathway analysis.

MeSH terms

CpG Islands / genetics*
DNA Methylation*
Gene Expression Profiling / methods*
Humans
Keloid / genetics*
Prospective Studies
Signal Transduction
Software