Asparagine starvation suppresses histone demethylation through iron depletion
Jie Jiang,
Sankalp Srivastava,
Sheng Liu,
Gretchen Seim,
Rodney Claude,
Minghua Zhong,
Sha Cao,
Utpal Davé,
Reuben Kapur,
Amber L. Mosley,
Chi Zhang,
Jun Wan,
Jing Fan,
Ji Zhang
Affiliations
Jie Jiang
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Sankalp Srivastava
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Sheng Liu
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Gretchen Seim
Morgridge Institute for Research and Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53715, USA
Rodney Claude
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Minghua Zhong
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Sha Cao
Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Utpal Davé
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Reuben Kapur
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Amber L. Mosley
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Chi Zhang
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Jun Wan
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Jing Fan
Morgridge Institute for Research and Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53715, USA
Ji Zhang
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Corresponding author
Summary: Intracellular α-ketoglutarate is an indispensable substrate for the Jumonji family of histone demethylases (JHDMs) mediating most of the histone demethylation reactions. Since α-ketoglutarate is an intermediate of the tricarboxylic acid cycle and a product of transamination, its availability is governed by the metabolism of several amino acids. Here, we show that asparagine starvation suppresses global histone demethylation. This process is neither due to the change of expression of histone-modifying enzymes nor due to the change of intracellular levels of α-ketoglutarate. Rather, asparagine starvation reduces the intracellular pool of labile iron, a key co-factor for the JHDMs to function. Mechanistically, asparagine starvation suppresses the expression of the transferrin receptor to limit iron uptake. Furthermore, iron supplementation to the culture medium restores histone demethylation and alters gene expression to accelerate cell death upon asparagine depletion. These results suggest that suppressing iron-dependent histone demethylation is part of the cellular adaptive response to asparagine starvation.
