Cell Reports (Oct 2023)
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
Affiliations
- Yimeng Gao
- 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; Corresponding author
- Joshua T. Zimmer
- 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
- Radovan Vasic
- 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
- Chengyang Liu
- 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
- Rana Gbyli
- 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
- Shu-Jian Zheng
- Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA; Department of Chemistry, Yale University, New Haven, CT 06520, USA
- Amisha Patel
- 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
- Wei Liu
- 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
- Zhihong Qi
- 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
- Yaping Li
- 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
- Raman Nelakanti
- Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
- Yuanbin Song
- 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
- Giulia Biancon
- 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
- Andrew Z. Xiao
- Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
- Sarah Slavoff
- 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
- Richard G. Kibbey
- Department of Internal Medicine, Yale University, New Haven, CT 06520, USA; Department of Cellular & Molecular Physiology, Yale University, New Haven, CT 06520, USA
- Richard A. Flavell
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Matthew D. Simon
- 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
- Toma Tebaldi
- 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
- Hua-Bing Li
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Stephanie Halene
- 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; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 10
p. 113163
Abstract
Summary: 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.
