Epigenetic activation of PERP transcription by MKL1 contributes to ROS-induced apoptosis in skeletal muscle cells

Zilong Li; Baoyu Chen; Wenhui Dong; Wenping Xu; Mingzi Song; Mingming Fang; Junli Guo; Yong Xu

doi:10.1016/j.bbagrm.2018.07.011

Epigenetic activation of PERP transcription by MKL1 contributes to ROS-induced apoptosis in skeletal muscle cells

Biochim Biophys Acta Gene Regul Mech. 2018 Jul 27:S1874-9399(18)30177-9. doi: 10.1016/j.bbagrm.2018.07.011. Online ahead of print.

Authors

Zilong Li¹, Baoyu Chen², Wenhui Dong², Wenping Xu³, Mingzi Song³, Mingming Fang³, Junli Guo⁴, Yong Xu⁵

Affiliations

¹ Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Institute of Biomedical Research, Liaocheng University, Liaocheng, China.
² Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
³ Department of Medicine, Jiangsu Health Vocational College, Nanjing, China.
⁴ Cardiovascular Disease and Research Institute, Affiliated Hospital of Hainan Medical College, Haikou, Hainan, China. Electronic address: guojl0511@126.com.
⁵ Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Institute of Biomedical Research, Liaocheng University, Liaocheng, China. Electronic address: yjxu@njmu.edu.cn.

PMID: 30056131
DOI: 10.1016/j.bbagrm.2018.07.011

Abstract

Excessive reactive oxygen species (ROS) causes irreparable damages to cells and commit cells to programmed cell death or apoptosis. A panel of well-documented pro-apoptotic genes, including p53 apoptosis effector related to PMP-22 (PERP), are up-regulated and collectively mediate ROS induced apoptosis. The epigenetic mechanism whereby ROS stimulates PERP transcription, however, lacks in-depth characterization. Here we report that the transcriptional modulator megakaryocytic leukemia 1 (MKL1) is activated by H₂O₂ treatment in skeletal muscle cells (C2C12). Small interfering RNA (siRNA) mediated silencing or small-molecule compound (CCG-1423) mediated inhibition of MKL1 attenuated H₂O₂ induced apoptosis of C2C12 cells. Over-expression of MKL1 potentiated trans-activation of PERP whereas MKL1 ablation/inhibition abrogated the induction of PERP by H₂O₂ in C2C12 cells. Mechanistically, MKL1 interacted with and was recruited to the PERP promoter by the transcription factor E2F1. Once bound to the PERP promoter, MKL1 engaged the histone demethylase KDM3A to modulate the chromatin structure surrounding the PERP promoter thereby leading to PERP trans-activation. Depletion of either E2F1 or KDM3A blocked the induction of PERP by H₂O₂. In conclusion, our data illustrate a novel epigenetic pathway that links PERP transcription to ROS-induced apoptosis in skeletal muscle cells.

Keywords: Apoptosis; Epigenetics; ROS; Transcriptional regulation.