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In American journal of physiology. Cell physiology

AIM : Ceiling culture-derived preadipocytes (ccdPAs) and adipose-derived stem cells (ASCs) can be harvested from human subcutaneous fat tissue using the specific gravity method. Both cell types possess a similar spindle shape without lipid droplets. We previously reported that ccdPAs have a higher adipogenic potential than ASCs, even after a 7-week culture. We performed a genome-wide epigenetic analysis to examine the mechanisms contributing to the adipogenic potential differences between ccdPAs and ASCs.

MATERIALS AND METHODS : Methylation analysis of cytosines followed by guanine (CpG) using a 450K BeadChip was performed on human ccdPAs and ASCs isolated from three metabolically healthy females. Chromatin immunoprecipitation sequencing (ChIP-seq) was performed to evaluate trimethylation at lysine 4 of histone 3 (H3K4me3).

RESULTS : Unsupervised machine learning using t-distributed stochastic neighbor embedding (tSNE) to interpret 450,000-dimensional methylation assay data showed that the cells were divided into ASC and ccdPA groups. In KEGG pathway analysis of 1,543 genes with differential promoter CpG methylation, the peroxisome proliferator-activated receptor (PPAR) and adipocytokine signaling pathways ranked in the top 10 pathways. In the PPAR gamma gene, H3K4me3 peak levels were higher in ccdPAs than in ASCs, whereas promoter CpG methylation levels were significantly lower in ccdPAs than in ASCs. Similar differences in promoter CpG methylation were also seen in the fatty acid-binding protein 4 (FABP4) and leptin genes.

CONCLUSION : We analyzed the epigenetic status of adipogenesis-related genes as a potential mechanism underlying the differences in adipogenic differentiation capability between ASCs and ccdPAs.

Kubota Yoshitaka, Nagano Hidekazu, Kosaka Kentaro, Ogata Hideyuki, Nakayama Akitoshi, Yokoyama Masataka, Murata Kazutaka, Akita Shinsuke, Kuriyama Motone, Furuyama Nobutaka, Kuroda Masayuki, Tanaka Tomoaki, Mitsukawa Nobuyuki


adipocyte, differentiation, epigenetics, histone, methylation