Alterations of sorbin and SH3 domain containing 3 (SORBS3) in human skeletal muscle following Roux-en-Y gastric bypass surgery

Samantha E. Day, Luis A. Garcia, Richard L. Coletta, Latoya E. Campbell, Tonya R. Benjamin, Elena A. De Filippis, James A. Madura, Lawrence J. Mandarino, Lori R. Roust, Dawn K. Coletta

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background: Obesity is a disease that is caused by genetic and environmental factors. However, epigenetic mechanisms of obesity are less well known. DNA methylation provides a mechanism whereby environmental factors can influence gene transcription. The aim of our study was to investigate skeletal muscle DNA methylation of sorbin and SH3 domain containing 3 (SORBS3) with weight loss induced by Roux-en-Y gastric bypass (RYGB). Results: Previously, we had shown increased methylation (5.0 to 24.4%) and decreased gene expression (fold change - 1.9) of SORBS3 with obesity (BMI > 30 kg/m2) compared to lean controls. In the present study, basal muscle biopsies were obtained from seven morbidly obese (BMI > 40 kg/m2) female subjects pre- and 3 months post-RYGB surgery, in combination with euglycemic-hyperinsulinemic clamps to assess insulin sensitivity. We identified 30 significantly altered promoter and untranslated region methylation sites in SORBS3 using reduced representation bisulfite sequencing (RRBS). Twenty-nine of these sites were decreased ( 5.6 to - 24.2%) post-RYGB compared to pre-RYGB. We confirmed the methylation in 2 (Chr.8:22,423,690 and Chr.8:22,423,702) of the 29 decreased SORBS3 sites using pyrosequencing. This decreased methylation was associated with an increase in SORBS3 gene expression (fold change + 1.7) post-surgery. In addition, we demonstrated that SORBS3 promoter methylation in vitro significantly alters reporter gene expression (P < 0.0001). Two of the SORBS3 methylation sites (Chr.8:22,423,111 and Chr.8:22,423,205) were strongly correlated with fasting plasma glucose levels (r = 0.9, P = 0.00009 and r = 0.8, P = 0.0010). Changes in SORBS3 gene expression post-surgery were correlated with obesity measures and fasting insulin levels (r = 0.5 to 0.8; P < 0.05). Conclusions: These results demonstrate that SORBS3 methylation and gene expression are altered in obesity and restored to normal levels through weight loss induced by RYGB surgery.

Original languageEnglish (US)
Article number96
JournalClinical Epigenetics
Volume9
Issue number1
DOIs
StatePublished - Sep 2 2017

Keywords

  • DNA methylation
  • Next-generation sequencing
  • Obesity
  • Skeletal muscle
  • Surgery

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

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    Day, S. E., Garcia, L. A., Coletta, R. L., Campbell, L. E., Benjamin, T. R., De Filippis, E. A., Madura, J. A., Mandarino, L. J., Roust, L. R., & Coletta, D. K. (2017). Alterations of sorbin and SH3 domain containing 3 (SORBS3) in human skeletal muscle following Roux-en-Y gastric bypass surgery. Clinical Epigenetics, 9(1), [96]. https://doi.org/10.1186/s13148-017-0396-5