Altered PTPRD DNA Methylation Associates with Restricted Adipogenesis in Healthy First-Degree Relatives of Type 2 Diabetes Subjects

Abstract

Aim: First-degree relatives (FDR) of individuals with Type 2 diabetes (T2D) feature restricted adipogenesis, which render them more vulnerable to T2D. Epigenetics may contribute to these abnormalities. Methods: FDR pre-adipocyte Methylome and Transcriptome were investigated by MeDIP- and RNA-Seq, respectively. Results:Methylome analysis revealed 2841 differentially methylated regions (DMR) in FDR. Most DMR localized into gene-body and were hypomethylated. The strongest hypomethylation signal was identified in an intronic-DMR at the PTPRD gene. PTPRD hypomethylation in FDR was confirmed by bisulphite sequencing and was responsible for its upregulation. Interestingly, Ptprd-overexpression in 3T3-L1 pre-adipocytes inhibited adipogenesis. Notably, the validated PTPRD-associated DMR was significantly hypomethylated in peripheral blood leukocytes from the same FDR individuals. Finally, PTPRD methylation pattern was also replicated in obese individuals. Conclusion: Our findings indicated a previously unrecognized role of PTPRD in restraining adipogenesis. This abnormality may contribute to increase FDR proclivity toward T2D.

Keywords::

• adipose tissue
• DNA methylation
• epigenetics
• gene expression
• pre-adipocyte
• Type 2 diabetes

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.comhttp://doi/suppl/10.2217/epi-2019-0267

Acknowledgments

The authors thank M Ceccarelli for his valuable support and comments.

Financial &competing interest disclosure

L Parrillo is the recipient of the SID-FO.DI.RI/MSD ITALIA 2017 Research Fellowship and the EFSD/Lilly Research Fellowship 2015. This study was funded, in part, by the European Foundation for the Study of Diabetes (EFSD), by the Ministero dell’Istruzione, Università e della Ricerca Scientifica, by Regione Campania POR FESR 2014–2020 (Obiettivo specific 1.2.) Manifestazione di Interesse per la Realizzazione di Technology Platform nell’ambito della Lotta alle Patologie Oncologiche” Projects: RARE PLAT NET, SATIN, and COEPICA, by the Società Italiana di Diabetologia (SID-FO.DI.RI), by the Swedish Research Council, Torsten Söderberg and by the Novo Nordisk Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval for all human experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

L Parrillo is the recipient of the SID-FO.DI.RI/MSD ITALIA 2017 Research Fellowship and the EFSD/Lilly Research Fellowship 2015. This study was funded, in part, by the European Foundation for the Study of Diabetes (EFSD), by the Ministero dell’Istruzione, Università e della Ricerca Scientifica, by Regione Campania POR FESR 2014–2020 (Obiettivo specific 1.2.) Manifestazione di Interesse per la Realizzazione di Technology Platform nell’ambito della Lotta alle Patologie Oncologiche” Projects: RARE PLAT NET, SATIN, and COEPICA, by the Società Italiana di Diabetologia (SID-FO.DI.RI), by the Swedish Research Council, Torsten Söderberg and by the Novo Nordisk Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.