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

doi:10.1016/j.isci.2023.106425

Asparagine starvation suppresses histone demethylation through iron depletion

iScience. 2023 Mar 16;26(4):106425. doi: 10.1016/j.isci.2023.106425. eCollection 2023 Apr 21.

Authors

Jie Jiang¹, Sankalp Srivastava^{1

2}, Sheng Liu³, Gretchen Seim⁴, Rodney Claude^{1

2}, Minghua Zhong¹, Sha Cao⁵, Utpal Davé⁶, Reuben Kapur¹, Amber L Mosley², Chi Zhang³, Jun Wan³, Jing Fan⁴, Ji Zhang^{1

2}

Affiliations

¹ Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
² Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
³ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁴ Morgridge Institute for Research and Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53715, USA.
⁵ Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁶ Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Abstract

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.

Keywords: Biological sciences; Epigenetics; Molecular biology; Molecular mechanism of gene regulation; Physiology.

Abstract

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