Role for carbohydrate response element-binding protein (ChREBP) in high glucose-mediated repression of long noncoding RNA Tug1

J Biol Chem. 2020 Nov 20;295(47):15840-15852. doi: 10.1074/jbc.RA120.013228. Epub 2020 May 28.

Abstract

Long noncoding RNAs (lncRNAs) have been shown to play key roles in a variety of biological activities of the cell. However, less is known about how lncRNAs respond to environmental cues and what transcriptional mechanisms regulate their expression. Studies from our laboratory have shown that the lncRNA Tug1 (taurine upregulated gene 1) is crucial for the progression of diabetic kidney disease, a major microvascular complication of diabetes. Using a combination of proximity labeling with the engineered soybean ascorbate peroxidase (APEX2), ChIP-qPCR, biotin-labeled oligonucleotide pulldown, and classical promoter luciferase assays in kidney podocytes, we extend our initial observations in the current study and now provide a detailed analysis on a how high-glucose milieu downregulates Tug1 expression in podocytes. Our results revealed an essential role for the transcription factor carbohydrate response element binding protein (ChREBP) in controlling Tug1 transcription in the podocytes in response to increased glucose levels. Along with ChREBP, other coregulators, including MAX dimerization protein (MLX), MAX dimerization protein 1 (MXD1), and histone deacetylase 1 (HDAC1), were enriched at the Tug1 promoter under high-glucose conditions. These observations provide the first characterization of the mouse Tug1 promoter's response to the high-glucose milieu. Our findings illustrate a molecular mechanism by which ChREBP can coordinate glucose homeostasis with the expression of the lncRNA Tug1 and further our understanding of dynamic transcriptional regulation of lncRNAs in a disease state.

Keywords: APEX2; CRISPR/Cas; ChREBP; Tug1; carbohydrate response element-binding protein (ChREBP); diabetic nephropathy; engineered soybean ascorbate peroxidase (APEX2); epigenetics; gene regulation; kidney; long noncoding RNA (lncRNA); taurine upregulated gene 1 (Tug1); transcription; transcription regulation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cell Line, Tumor
  • Gene Expression Regulation*
  • Glucose / genetics
  • Glucose / metabolism*
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Humans
  • Mice
  • Podocytes / metabolism*
  • RNA, Long Noncoding / biosynthesis*
  • RNA, Long Noncoding / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Transcription, Genetic*

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Mad protein, mouse
  • Mlxipl protein, mouse
  • RNA, Long Noncoding
  • Repressor Proteins
  • long non-coding RNA TUG1, mouse
  • Hdac1 protein, mouse
  • Histone Deacetylase 1
  • Glucose