Hypoxia-inducible factor 1 recruits FACT and RNF20/40 to mediate histone ubiquitination and transcriptional activation of target genes
Yajing Lyu,
Yongkang Yang,
Varen Talwar,
Haiquan Lu,
Chelsey Chen,
Shaima Salman,
Elizabeth E. Wicks,
Tina Yi-Ting Huang,
Daiana Drehmer,
Yufeng Wang,
Qiaozhu Zuo,
Emmanuel Datan,
Walter Jackson, III,
Dominic Dordai,
Ru Wang,
Gregg L. Semenza
Affiliations
Yajing Lyu
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Yongkang Yang
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21205, USA
Varen Talwar
Johns Hopkins University, Baltimore, MD 21218, USA
Haiquan Lu
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21205, USA
Chelsey Chen
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Shaima Salman
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Elizabeth E. Wicks
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Tina Yi-Ting Huang
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Daiana Drehmer
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Yufeng Wang
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Qiaozhu Zuo
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Emmanuel Datan
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Walter Jackson, III
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Dominic Dordai
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Ru Wang
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Gregg L. Semenza
Armstrong Oxygen Biology Research Center and Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21205, USA; Corresponding author
Summary: Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator that mediates cellular adaptation to decreased oxygen availability. HIF-1 recruits chromatin-modifying enzymes leading to changes in histone acetylation, citrullination, and methylation at target genes. Here, we demonstrate that hypoxia-inducible gene expression in estrogen receptor (ER)-positive MCF7 and ER-negative SUM159 human breast cancer cells requires the histone H2A/H2B chaperone facilitates chromatin transcription (FACT) and the H2B ubiquitin ligase RING finger protein 20/40 (RNF20/40). Knockdown of FACT or RNF20/40 expression leads to decreased transcription initiation and elongation at HIF-1 target genes. Mechanistically, FACT and RNF20/40 are recruited to hypoxia response elements (HREs) by HIF-1 and stabilize binding of HIF-1 (and each other) at HREs. Hypoxia induces the monoubiquitination of histone H2B at lysine 120 at HIF-1 target genes in an HIF-1-dependent manner. Together, these findings delineate a cooperative molecular mechanism by which FACT and RNF20/40 stabilize multiprotein complex formation at HREs and mediate histone ubiquitination to facilitate HIF-1 transcriptional activity.
