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2014 ; 9
(10
): 1339-49
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Genome-wide DNA methylation analysis identifies a metabolic memory profile in
patient-derived diabetic foot ulcer fibroblasts
#MMPMID25437049
Park LK
; Maione AG
; Smith A
; Gerami-Naini B
; Iyer LK
; Mooney DJ
; Veves A
; Garlick JA
Epigenetics
2014[Oct]; 9
(10
): 1339-49
PMID25437049
show ga
Diabetic foot ulcers (DFUs) are a serious complication of diabetes. Previous
exposure to hyperglycemic conditions accelerates a decline in cellular function
through metabolic memory despite normalization of glycemic control. Persistent,
hyperglycemia-induced epigenetic patterns are considered a central mechanism that
activates metabolic memory; however, this has not been investigated in
patient-derived fibroblasts from DFUs. We generated a cohort of patient-derived
lines from DFU fibroblasts (DFUF), and site- and age-matched diabetic foot
fibroblasts (DFF) and non-diabetic foot fibroblasts (NFF) to investigate global
and genome-wide DNA methylation patterns using liquid chromatography/mass
spectrometry and the Illumina Infinium HumanMethylation450K array. DFFs and DFUFs
demonstrated significantly lower global DNA methylation compared to NFFs (p =
0.03). Hierarchical clustering of differentially methylated probes (DMPs, p =
0.05) showed that DFFs and DFUFs cluster together and separately from NFFs.
Twenty-five percent of the same probes were identified as DMPs when individually
comparing DFF and DFUF to NFF. Functional annotation identified enrichment of
DMPs associated with genes critical to wound repair, including angiogenesis (p =
0.07) and extracellular matrix assembly (p = 0.035). Identification of sustained
DNA methylation patterns in patient-derived fibroblasts after prolonged passage
in normoglycemic conditions demonstrates persistent metabolic memory. These
findings suggest that epigenetic-related metabolic memory may also underlie
differences in wound healing phenotypes and can potentially identify therapeutic
targets.