Differential m6A RNA landscapes across hematopoiesis reveal a role for IGF2BP2 in preserving hematopoietic stem cell function

Rong Yin; Jiwei Chang; Yashu Li; Zhuying Gao; Qiang Qiu; Qifan Wang; Guoqiang Han; Jihua Chai; Mengdie Feng; Peipei Wang; Tiantian Zhang; Xueqin Xie; Jin Hu; Ying Cheng; Chengli Guo; Jing Wang; Kexin Gao; Manman Cui; Shaoguang Li; Yuhuan Zheng; Wei Jiang; Yiguo Hu; Qing-Yong Yang; Haojian Zhang

doi:10.1016/j.stem.2021.09.014

Differential m⁶A RNA landscapes across hematopoiesis reveal a role for IGF2BP2 in preserving hematopoietic stem cell function

Cell Stem Cell. 2022 Jan 6;29(1):149-159.e7. doi: 10.1016/j.stem.2021.09.014. Epub 2021 Oct 21.

Authors

Rong Yin¹, Jiwei Chang², Yashu Li³, Zhuying Gao², Qiang Qiu⁴, Qifan Wang², Guoqiang Han², Jihua Chai⁵, Mengdie Feng², Peipei Wang², Tiantian Zhang², Xueqin Xie², Jin Hu², Ying Cheng², Chengli Guo⁵, Jing Wang⁵, Kexin Gao², Manman Cui², Shaoguang Li⁶, Yuhuan Zheng⁷, Wei Jiang², Yiguo Hu⁴, Qing-Yong Yang⁸, Haojian Zhang⁹

Affiliations

¹ The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China; RNA Institute, Wuhan University, Wuhan, China.
² Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
³ The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
⁴ Department of Thyroid Surgery and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
⁵ The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
⁶ Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
⁷ Department of Hematology, West China School of Medicine, Sichuan University, Chengdu, China.
⁸ Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China.
⁹ The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China; RNA Institute, Wuhan University, Wuhan, China. Electronic address: haojian_zhang@whu.edu.cn.

PMID: 34678169
DOI: 10.1016/j.stem.2021.09.014

Abstract

N⁶-methyladenosine (m⁶A) on mRNA plays critical roles in various cellular processes. However, the landscape and dynamics of m⁶A modification in hematopoietic system remain unknown. Here, we delineate a comprehensive m⁶A landscape across hematopoietic hierarchy and uncover that IGF2BP2 is required for preserving the function of hematopoietic stem cells (HSCs). Our data reveal a cell-type-specific m⁶A landscape in hematopoiesis. m⁶A modifications arise mostly in the early stage of hematopoiesis and prefer to play distinct roles for determining mRNA fates in HSCs and committed progenitors. Mechanistically, increased m⁶A-IGF2BP2 expression controls transcriptional state and maintenance of HSCs. IGF2BP2 deficiency induces quiescence loss and impairs HSC function. Moreover, IGF2BP2 loss increases mitochondrial activity of HSCs by accelerating Bmi1 mRNA decay, leading to de-repression of mitochondria-related genes. Collectively, our results present a fascinating portrait of m⁶A modification of hematopoietic hierarchy and reveal a key role of IGF2BP2 in maintaining HSC function by restraining mitochondrial activity.

Keywords: IGF2BP2; N6-methyladenosine; hematopoiesis; hematopoietic stem cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Division
Hematopoiesis* / genetics
Hematopoietic Stem Cells / metabolism
Mitochondria
RNA* / metabolism

Substances

RNA