Hepatocyte nuclear factor 1 alpha (HNF1A) regulates transcription of O-GlcNAc transferase in a negative feedback mechanism

FEBS Lett. 2019 May;593(10):1050-1060. doi: 10.1002/1873-3468.13381. Epub 2019 May 14.

Abstract

O-GlcNAc transferase (OGT)-catalyzed protein O-GlcNAcylation is implicated in diverse cellular events. In the present study, we report the regulation of ogt transcription by the hepatocyte nuclear factor 1 homologue A (HNF1A) in HEK293T cells. We first identified a core ogt promoter (-150 to +200 bp) and confirmed its binding to the transcription factor HNF1A. We found that HNF1A regulates ogt transcription in a time-dependent manner and that O-GlcNAcylation of HNF1A represses ogt transcription. Electron-transfer dissociation based tandem mass spectrometry analysis revealed 14 O-GlcNAc sites on HNF1A, six of which are predominantly modified, including Ser303/304 , Ser471 , Ser560 and Thr563/564 . We further found that loss of O-GlcNAcylation at Ser303/304 or Thr563/564 significantly elevates ogt transcription. These findings highlight a negative feedback mechanism for ogt transcription, which partially explains the homeostasis of cellular O-GlcNAcylation.

Keywords: OGT; HNF1A; negative feedback mechanism; transcriptional regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Feedback, Physiological*
  • Gene Expression Regulation*
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 1-alpha / metabolism*
  • Humans
  • N-Acetylglucosaminyltransferases / genetics*
  • N-Acetylglucosaminyltransferases / metabolism
  • Protein Processing, Post-Translational*
  • Substrate Specificity
  • Tandem Mass Spectrometry
  • Transcription, Genetic

Substances

  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • N-Acetylglucosaminyltransferases
  • OGT protein, human

Associated data

  • GENBANK/XM_017029908.1