Epigenetic regulation of DOT1L methyltransferase activity remodels lipid metabolism to alleviate ferroptosis-induced liver injury
Jia-ming Hu, Shuo Liu, Zheng-ze Pan, Yi-jia Gao, Wei-wei Cui, Xiao Zhuang, Rong Wang, Ya-jing Han, Jia-xing Liu, Xiang-chuang Fan, Dan-dan Song, Zi-yang Zhang, Wan-yang Sun, Zong-li Zhang, Rong-rong He, Yun-fei Xu, Wei Gu, Chang Pan, Bo Chu
Jia-ming Hu, Shuo Liu, Zheng-ze Pan, Yi-jia Gao, Wei-wei Cui, Xiao Zhuang, Rong Wang, Ya-jing Han, Jia-xing Liu, Xiang-chuang Fan, Dan-dan Song, Zi-yang Zhang, Wan-yang Sun, Zong-li Zhang, Rong-rong He, Yun-fei Xu, Wei Gu, Chang Pan, Bo Chu
View: Text | PDF
Research In-Press Preview Cell biology Hepatology Metabolism

Epigenetic regulation of DOT1L methyltransferase activity remodels lipid metabolism to alleviate ferroptosis-induced liver injury

Abstract

Epigenetic modifications contribute to lipid-related disorders by modulating the expression of key genes involved in lipid metabolism. Accumulating evidence suggests that lipid metabolism-mediated ferroptosis drives the progression of metabolic associated steatohepatitis (MASH) and liver injury. However, whether epigenetic mechanisms remodel lipid metabolism to regulate ferroptosis-induced liver damage remains unclear. Here, through pharmacological screening of epigenetics-related compounds and CRISPR-Cas9-based screening targeting epigenetic factors, we identified DOT1 Like Histone Lysine Methyltransferase (DOT1L) as a key sensitizer of hepatocytes to ferroptosis and subsequent liver injury, whereas inhibition of DOT1L reverses the phenomenon. DOT1L loss remodeled the phospholipid landscape by decreasing PUFA-containing phospholipids while increasing monounsaturated and lysophospholipid species. Mechanistically, DOT1L depletion reduced H3K79me1 and H3K79me2 occupancy at the PLA2G7, ALDH3B1, and PLCXD3 loci, particularly across gene-body regions, while increasing promoter-proximal accessibility and expression of these phospholipid-remodeling genes. These genes suppress ferroptosis by reducing the levels of phospholipids containing polyunsaturated fatty acids (PL-PUFAs). Furthermore, we demonstrated that AMPK phosphorylates DOT1L at Ser786, weakens its association with AF9, and suppresses H3K79 methyltransferase activity and ferroptosis sensitivity. Collectively, our findings reveal the AMPK–DOT1L–H3K79 methylation axis as a novel lipid metabolic pathway that regulates ferroptosis and maintains hepatic homeostasis, offering new therapeutic insights for ferroptosis-related liver injury.

Authors

Jia-ming Hu, Shuo Liu, Zheng-ze Pan, Yi-jia Gao, Wei-wei Cui, Xiao Zhuang, Rong Wang, Ya-jing Han, Jia-xing Liu, Xiang-chuang Fan, Dan-dan Song, Zi-yang Zhang, Wan-yang Sun, Zong-li Zhang, Rong-rong He, Yun-fei Xu, Wei Gu, Chang Pan, Bo Chu

×
Problems with a PDF?

This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.

Having trouble reading a PDF?

PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.

Having trouble saving a PDF?

Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.

Having trouble printing a PDF?

  1. Try printing one page at a time or to a newer printer.
  2. Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
  3. Make sure you are using the latest version of Adobe's Acrobat Reader.

- Download (10.38 MB)

Advertisement