ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control

Yimeng Gao; Joshua T Zimmer; Radovan Vasic; Chengyang Liu; Rana Gbyli; Shu-Jian Zheng; Amisha Patel; Wei Liu; Zhihong Qi; Yaping Li; Raman Nelakanti; Yuanbin Song; Giulia Biancon; Andrew Z Xiao; Sarah Slavoff; Richard G Kibbey; Richard A Flavell; Matthew D Simon; Toma Tebaldi; Hua-Bing Li; Stephanie Halene

doi:10.1016/j.celrep.2023.113163

ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m⁶A modification-mediated RNA stability control

Cell Rep. 2023 Oct 31;42(10):113163. doi: 10.1016/j.celrep.2023.113163. Epub 2023 Sep 23.

Authors

Yimeng Gao¹, Joshua T Zimmer², Radovan Vasic³, Chengyang Liu⁴, Rana Gbyli⁵, Shu-Jian Zheng⁶, Amisha Patel⁴, Wei Liu⁴, Zhihong Qi⁴, Yaping Li⁴, Raman Nelakanti⁷, Yuanbin Song⁸, Giulia Biancon⁴, Andrew Z Xiao⁷, Sarah Slavoff⁹, Richard G Kibbey¹⁰, Richard A Flavell¹¹, Matthew D Simon², Toma Tebaldi¹², Hua-Bing Li¹³, Stephanie Halene¹⁴

Affiliations

¹ Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: gaoym@tongji.edu.cn.
² Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06511, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA.
³ Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Medicine, University of Toronto, Toronto, ON M5S3H2, Canada.
⁴ Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
⁵ Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
⁶ Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA; Department of Chemistry, Yale University, New Haven, CT 06520, USA.
⁷ Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
⁸ Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
⁹ Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06511, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA; Department of Chemistry, Yale University, New Haven, CT 06520, USA.
¹⁰ Department of Internal Medicine, Yale University, New Haven, CT 06520, USA; Department of Cellular & Molecular Physiology, Yale University, New Haven, CT 06520, USA.
¹¹ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
¹² Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
¹³ Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
¹⁴ Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: stephanie.halene@yale.edu.

Abstract

N⁶-methyladenosine (m⁶A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m⁶A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m⁶A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and instability of oxoglutarate-dehydrogenase (Ogdh) messenger RNA and reduction of OGDH protein levels. Limited OGDH availability slows the tricarboxylic acid (TCA) cycle with accumulation of α-ketoglutarate (α-KG) and conversion of α-KG into L-2-hydroxyglutarate (L-2-HG). L-2-HG inhibits energy production in both murine and human hematopoietic cells in vitro. Impaired mitochondrial energy production confers competitive disadvantage to HSPCs and limits clonogenicity of Mll-AF9-induced leukemia. Our study uncovers a mechanism whereby the RNA m⁶A demethylase ALKBH5 regulates the stability of metabolic enzyme transcripts, thereby controlling energy metabolism in hematopoiesis and leukemia.

Keywords: ALKBH5; ATP production; CP: Molecular biology; CP: Stem cell research; OXPHOS; RNA stability; energy metabolism; hematopoietic stem and progenitor cells; leukemia; m(6)A modification; oxidative phosphorylation; stress hematopoiesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AlkB Homolog 5, RNA Demethylase / genetics
AlkB Homolog 5, RNA Demethylase / metabolism
Animals
Energy Metabolism
Hematopoietic Stem Cells / metabolism
Humans
Leukemia*
Mice
RNA Stability / genetics
RNA* / metabolism

Substances

AlkB Homolog 5, RNA Demethylase
ALKBH5 protein, human
RNA
ALKBH5 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding