TET2-interacting long noncoding RNA promotes active DNA demethylation of the MMP-9 promoter in diabetic wound healing

Liyan Zhou,Li Yan,Wei Wang,Tingting Zeng,Kan Sun,Shicheng Su,Mengdie Hu,Jing Liu,Chuan Yang,Chuan Wang,Meng Ren,Xiaoyi Wang

doi:10.1038/s41419-019-2047-6

Abstract

Wound healing in diabetic skin is impaired by excessive activation of matrix metalloproteinase-9 (MMP-9). MMP-9 transcription is activated by Ten-eleven translocation 2 (TET2), a well-known DNA demethylation protein that induces MMP-9 promoter demethylation in diabetic skin tissues. However, how TET2 is targeted to specific loci in the MMP-9 promoter is unknown. Here, we identified a TET2-interacting long noncoding RNA (TETILA) that is upregulated in human diabetic skin tissues. TETILA regulates TET2 subcellular localization and enzymatic activity, indirectly activating MMP-9 promoter demethylation. TETILA also recruits thymine-DNA glycosylase (TDG), which simultaneously interacts with TET2, for base excision repair-mediated MMP-9 promoter demethylation. Together, our results suggest that the TETILA serves as a genomic homing signal for TET2-mediated demethylation specific loci in MMP-9 promoter, thereby disrupting the process of diabetic skin wound healing.

Highlights

Diabetic foot ulcers (DFUs) are major complication of diabetes[1,2]
Identification of a Ten-eleven translocation 2 (TET2)-binding Long noncoding RNA (lncRNA) We first analyzed different lncRNA expression patterns, which bound to TET2 protein between bovine serum albumin (BSA)- and Advanced glycation end-products (AGEs)-treated group in HaCaT cells (Fig. S1a)
We found lncRNAG072813 was the highest enriched in TET2-RNA precipitates (Fig. 1a)

Summary

Introduction

High blood sugar triggers prolonged chronic inflammation with concomitant elevated levels of matrix metalloproteinases (MMPs) in diabetic patients. The excess protease activity can lead to delay diabetic wound healing and result in limb amputation, especially matrix metalloproteinase-9 (MMP-9), which was present in more than 50% of the chronic wounds[4,5,6]. Increasing studies have revealed that MMP-9 expression is critically mediated by epigenetic mechanisms, including histone modification, DNA methylation, and noncoding RNA5,10. It is an important approach to use AGEs to mimic diabetic conditions in vitro, especially the epigenetic mechanisms of diabetic complication[11,12]. We published that AGEs induce binding of the protein Ten-eleven translocation 2 (TET2) to the MMP-9 promoter and impair diabetic wound healing[13]. The molecular mechanisms underlying how TET2 is targeted to MMP-9 promoter-specific loci in diabetic skin cells remain unresolved

Methods

Results

Conclusion