The Methylation Analysis of the Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) Locus in GH-Secreting Pituitary Adenomas

Author:

Dalle Nogare Mattia1ORCID,D’Annunzio Sarah2,Vazza Giovanni1,Regazzo Daniela3ORCID,Picello Luna1,Denaro Luca4ORCID,Voltan Giacomo3,Scaroni Carla3,Ceccato Filippo3ORCID,Occhi Gianluca1ORCID

Affiliation:

1. Department of Biology, University of Padova, 35128 Padova, Italy

2. Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy

3. Endocrinology Unit, Department of Medicine, Padova University Hospital, 35121 Padova, Italy

4. Academic Neurosurgery, Department of Neurosciences, Padova University Hospital, 35121 Padova, Italy

Abstract

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is aberrantly expressed in about one-third of GH-secreting pituitary adenomas (GH-PAs) and has been associated with a paradoxical increase of GH after a glucose load. The reason for such an overexpression has not yet been clarified. In this work, we aimed to evaluate whether locus-specific changes in DNA methylation patterns could contribute to this phenomenon. By cloning bisulfite-sequencing PCR, we compared the methylation pattern of the GIPR locus in GIPR-positive (GIPR+) and GIPR-negative (GIPR−) GH-PAs. Then, to assess the correlation between Gipr expression and locus methylation, we induced global DNA methylation changes by treating the lactosomatotroph GH3 cells with 5-aza-2′-deoxycytidine. Differences in methylation levels were observed between GIPR+ and GIPR− GH-PAs, both within the promoter (31.9% vs. 68.2%, p < 0.05) and at two gene body regions (GB_1 20.7% vs. 9.1%; GB_2 51.2% vs. 65.8%, p < 0.05). GH3 cells treated with 5-aza-2′-deoxycytidine showed a ~75% reduction in Gipr steady-state level, possibly associated with the observed decrease in CpGs methylation. These results indicate that epigenetic regulation affects GIPR expression in GH-PAs, even though this possibly represents only a part of a much more complex regulatory mechanism.

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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