DOT1L/H3K79me2 represses HIV-1 reactivation via recruiting DCAF1
Fenfei Liang,
Jiaxing Jin,
Qiming Li,
Jiangkai Duan,
Ao Jiang,
Xiaoqing Chen,
Huichao Geng,
Kai Wu,
Fei Yu,
Xiaolu Zhao,
Yu Zhou,
Deqing Hu,
Liang Chen
Affiliations
Fenfei Liang
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
Jiaxing Jin
State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
Qiming Li
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
Jiangkai Duan
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
Ao Jiang
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
Xiaoqing Chen
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
Huichao Geng
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
Kai Wu
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
Fei Yu
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
Xiaolu Zhao
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
Yu Zhou
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China
Deqing Hu
State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Cancer Institute and Hospital of Tianjin Medical University, Tianjin 300060, China; Corresponding author
Liang Chen
RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China; Corresponding author
Summary: DOT1L mediates the methylation of histone H3 at lysine 79 and, in turn, the transcriptional activation or repression in a context-dependent manner, yet the regulatory mechanisms and functions of DOT1L/H3K79me remain to be fully explored. Following peptide affinity purification and proteomic analysis, we identified that DCAF1—a component of the E3 ligase complex involved in HIV regulation—is associated with H3K79me2 and DOT1L. Interestingly, blocking the expression or catalytic activity of DOT1L or repressing the expression of DCAF1 significantly enhances the tumor necrosis factor alpha (TNF-α)/nuclear factor κB (NF-κB)-induced reactivation of the latent HIV-1 genome. Mechanistically, upon TNF-α/NF-κB activation, DCAF1 is recruited to the HIV-1 long terminal repeat (LTR) by DOT1L and H3K79me2. Recruited DCAF1 subsequently induces the ubiquitination of NF-κB and restricts its accumulation at the HIV-1 LTR. Altogether, our findings reveal a feedback modulation of HIV reactivation by DOT1L-mediated histone modification regulation and highlight the potential of targeting the DOT1L/DCAF1 axis as a therapeutic strategy for HIV treatment.
