Regulation of shelterin proteins TERF2IP and TRF2 by H3K4me3-p65 axis drives hyperglycemia dependent endothelial senescence

Author:

Thakar Sumukh,Bhattacharya Ritobrata,Katakia Yash T,Chakraborty Srinjoy,Ramakrishnan S,Thakkar Niyati Pandya,Dey Smita,Chowdhury Shibasish,Majumder SyamantakORCID

Abstract

AbstractBackgroundEndothelial senescence has been linked to several cardiovascular diseases. Dysregulation of proteins of the shelterin complex including TRF2 and TERF2IP causes senescence as it hampers DNA repair and cell proliferation. However, whether exposure to hyperglycemia interplays with proteins of the shelterin complex thus further dictates the senescent phenotype of endothelial cells (EC) remain to be explored.Approach and ResultsIn this study, we observed elevated levels of p21 and p53 in endothelial cells upon exposure to intermittent hyperglycemia. We also noted hyperglycemia exposure increased the levels of TERF2IP and TRF2, part of the shelterin complex. No change in the level of TRF1 and TPP1 were detected. Furthermore, a robust induction was detected in p65 level upon intermittent hyperglycemia challenge. ChIP-qPCR analysis revealed enhanced H3K4me3 enrichment in the promoter regions of p65, TERF2IP and TRF2. Inhibition of catalysis of H3K4me3 either by pharmacological inhibitor or siRNA-mediated knockdown of MLL2 attenuated increase in p65, TERF2IP and TRF2 levels including reversal of senescence markers p53 and p21. Interestingly, pharmacological inhibition of NF-κB signaling also diminished abrupt increase in TERF2IP and TRF2 levels thus further reversed intermittent hyperglycemia-induced p53 and p21 levels. More importantly, co-immunoprecipitation and co-localization analysis revealed an interaction between nuclear p65 and MLL2 in EC stimulated with hyperglycemia. Further knockdown of either TERF2IP or TRF2 impaired intermittent hyperglycemia-induced p53 and p21 expression and associated endothelial senescence.ConclusionOverall, the present study describes an interplay of epigenetics in defining NF-κB signaling and shelterin proteins’ expression which further govern the biochemical and functional state of endothelial senescence in hyperglycemic milieu.

Publisher

Cold Spring Harbor Laboratory

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