Leptin Induces Epigenetic Regulation of Transient Receptor Potential Melastatin 7 in PC12 Cells

Bonnie Ho-Yee Yeung, Kelly Griffiths, Liron Berger, Omkar Paudel, Mi-Kyung Shin, Liangyou Rui, James S K Sham, Vsevolod Y Polotsky, Wan-Yee Tang
American Journal of Respiratory Cell and Molecular Biology 2021 April 23
Obesity elevates plasma level of leptin, which has been associated with hypertension. Our recent studies in mice demonstrated that leptin increases blood pressure by activating the carotid sinus nerve, which transmits the chemosensory input from carotid bodies (CB) to the medullary centers; and the effect of leptin is mediated via transient receptor potential melastatin 7 (Trpm7) channels in CB glomus cells. We also found that Trpm7 overexpression and Trpm7 promoter demethylation in CB correlate positively with the hyperleptinemia and leptin receptor overexpression in CB. Hence, we postulated that leptin epigenetically regulates Trpm7 expression in CB. We addressed our hypothesis utilizing the undifferentiated rat pheochromocytoma (PC12) cells as a model of CB glomus cells. PC12 cells (PC12LEPRb) expressing the long active form of leptin-receptor (LEPRb) showed dramatic induction of the promoter activity and expression of Trpm7 upon leptin treatment. The increased Trpm7 expression coincided with the reduction in CpG site-specific methylation and tri-methylation of histone 3 (H3) lysine (K) 27 (H3K27M3), and the increase in acetylation of H3K27 (H3K27Ac) and tri-methylation of H3K4 (H3K4M3) at the Trpm7 promoter. The inhibitor of STAT3 signaling, SD1008, reversed the leptin-induced Trpm7 promoter activity via modulations in bindings of pSTAT3 and DNMT3B and modifications of H3K27 and H3K4 at the Trpm7 promoter. Our results suggest that leptin-activated pSTAT3 epigenetically regulates the transcription of Trpm7 through DNA methylation and histone modifications. As epigenetic changes are reversible, targeting epigenetic modifications of Trpm7 may serve as a new therapeutic approach for the treatment of hypertension in obesity.

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