UTX-1 regulates Tat-induced HIV-1 transactivation via changing the methylated status of histone H3.
Epigenetic modifications are thought to be important for gene expression changes during HIV-1 transcription and replication. The removal of histone H3 lysine27 (H3K27) trimethylation mark by UTX-1 is important for the robust induction of many specific genes during Tat-mediated HIV-1 transactvation. We found that UTX-1 enzymatic activity is needed for Tat to remove a repressive mark H3K27me3 in the HIV-1 long terminal repeat (LTR). UTX-1 converted the chromatin structure to a more transcriptionally active state by up-regulation of H3K4 methylation and down-regulation of H3K27 methylation on the specific regions of HIV-1 LTR. The increase in H3K27me3 and the decrease in H3K4me3 induced by UTX-1 knockdown was detected on the HIV-1 LTR, but not by control siRNA. Additionally, UTX-1 promotes HIV-1 gene expression by enhancing both the NF-κB p65's nuclear translocation and its p65 binding to HIV-1 LTR. And we further demonstrated that H3K27 demethylase activity was required for increased HIV-1 transactivation induced by UTX-1. Together, our data reveal key roles for UTX-1 in a timely transition from poised to active chromatin in HIV-1 LTR during HIV-1 transcription and a fundamental mechanism by which a H3K27 demethylase triggers tissue-specific chromatin changes. Our findings provide a mechanistic link between UTX-1 and enhanced HIV-1 replication, and suggest that targeting at epigenetic mechanism may have a therapeutic benefit for HIV-1 patients.
College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124,China. Electronic address: zhanghs@bjut.edu.cn.
Hong-Sheng
HS
Zhang
College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124,China.
Guang-Yuan
GY
Du
College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124,China.
Yang
Y
Liu
College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124,China.
Zhong-Guo
ZG
Zhang
College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124,China.
Zhen
Z
Zhou
College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124,China.
Hu
H
Li
College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124,China.
Ke-Qing
KQ
Dai
College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124,China.
Xiao-Ying
XY
Yu
College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124,China.
Xiao-Meng
XM
Gou
D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics*; D006367:HeLa Cells; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D006657:Histones; D016328:NF-kappa B; D009687:Nuclear Proteins; D051996:Transcription Factor RelA; D054322:tat Gene Products, Human Immunodeficiency Virus; D056466:Histone Demethylases; C523998:KDM6A protein, human; D008239:Lysine
H3K27me3; HIV-1; Tat; UTX-1