TET2 suppresses vascular calcification by forming inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation

Dayu He; Jianshuai Ma; Ziting Zhou; Yanli Qi; Yaxin Lian; Feng Wang; Huiyong Yin; Huanji Zhang; Tingting Zhang; Hui Huang

doi:10.1172/JCI186673

TET2 suppresses vascular calcification by forming inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation

Dayu He,¹ Jianshuai Ma,¹ Ziting Zhou,¹ Yanli Qi,¹ Yaxin Lian,¹ Feng Wang,¹ Huiyong Yin,² Huanji Zhang,¹ Tingting Zhang,¹ and Hui Huang¹

Published March 11, 2025 - More info

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Abstract

Osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) has been recognized as the principal mechanism underlying vascular calcification (VC). Runt-related transcription factor 2 (RUNX2) in VSMCs plays a pivotal role because it constitutes an essential osteogenic transcription factor for bone formation. As a key DNA demethylation enzyme, ten-eleven translocation 2 (TET2) is crucial in maintaining the VSMC phenotype. However, whether TET2 involves in VC progression remains elusive. Here we identified a substantial downregulation of TET2 in calcified human and mouse arteries, as well as human primary VSMCs. In vitro gain- and loss-of function experiments demonstrated TET2 regulated VC. Subsequently, in vivo knockdown of TET2 significantly exacerbated VC in both vitamin D3 and adenine-diet-induced chronic kidney disease (CKD) mice models. Mechanistically, TET2 binds to and suppresses the activity of the P2 promoter within the RUNX2 gene, whereas an enzymatic loss-of-function mutation of TET2 has a comparable effect. Furthermore, TET2 forms a complex with histone deacetylases 1/2 (HDAC1/2 ) to deacetylate H3K27ac on the P2 promoter, thereby inhibiting its transcription. Moreover, SNIP1 is indispensable for TET2 to interact with HDAC1/2 to exert inhibitory effect on VC, and knockdown of SNIP1 accelerated VC in mice. Collectively, our findings imply that TET2 might serve as a potential therapeutic target for VC.

TET2 suppresses vascular calcification by forming inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation

Dayu He,¹ Jianshuai Ma,¹ Ziting Zhou,¹ Yanli Qi,¹ Yaxin Lian,¹ Feng Wang,¹ Huiyong Yin,² Huanji Zhang,¹ Tingting Zhang,¹ and Hui Huang¹

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TET2 suppresses vascular calcification by forming inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation

Dayu He,1 Jianshuai Ma,1 Ziting Zhou,1 Yanli Qi,1 Yaxin Lian,1 Feng Wang,1 Huiyong Yin,2 Huanji Zhang,1 Tingting Zhang,1 and Hui Huang1

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Dayu He,¹ Jianshuai Ma,¹ Ziting Zhou,¹ Yanli Qi,¹ Yaxin Lian,¹ Feng Wang,¹ Huiyong Yin,² Huanji Zhang,¹ Tingting Zhang,¹ and Hui Huang¹