Polycomb group protein Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of self-renewal and proliferation genes

Wenjie Cai; Xicheng Liu; Sergio Barajas; Shiyu Xiao; Sasidhar Vemula; Hongxia Chen; Yuxia Yang; Christopher Bochers; Danielle Henley; Sheng Liu; Yuzhi Jia; Michelle Hong; Tiffany M Mays; Maegan L Capitano; Huiping Liu; Peng Ji; Zhonghua Gao; Diego Pasini; Jun Wan; Feng Yue; Leonidas C Platanias; Rongwen Xi; Sisi Chen; Yan Liu

doi:10.1038/s41375-024-02462-w

Polycomb group protein Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of self-renewal and proliferation genes

Leukemia. 2024 Nov 19. doi: 10.1038/s41375-024-02462-w. Online ahead of print.

Authors

Wenjie Cai^{1

2}, Xicheng Liu³, Sergio Barajas^{1

2}, Shiyu Xiao¹, Sasidhar Vemula⁴, Hongxia Chen^{2

5}, Yuxia Yang^{4

6}, Christopher Bochers², Danielle Henley⁴, Sheng Liu⁷, Yuzhi Jia⁸, Michelle Hong¹, Tiffany M Mays¹, Maegan L Capitano⁹, Huiping Liu^{8

10}, Peng Ji^{10

11}, Zhonghua Gao¹², Diego Pasini^{13

14}, Jun Wan⁷, Feng Yue^{10

15}, Leonidas C Platanias^{1

10}, Rongwen Xi³, Sisi Chen^{16

17}, Yan Liu^{18

19

20}

Affiliations

¹ Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
² Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
³ National Institute of Biological Science, Beijing, China.
⁴ Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
⁵ Department of Hematology and Oncology, Chongqing University Three Gorges Hospital, Chongqing, China.
⁶ Department of Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, China.
⁷ Department of Medical Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
⁸ Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
⁹ Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
¹⁰ Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, 60611, USA.
¹¹ Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
¹² Department of Biochemistry and Molecular Biology, College of Medicine, Pennsylvania State University, Hershey, PA, 17033, USA.
¹³ European Institute of Oncology IRCCS, Department of Experimental Oncology, Via Adamello 16, 20139, Milan, Italy.
¹⁴ University of Milan, Department of Health Sciences, Via A. di Rudinì 8, 20142, Milan, Italy.
¹⁵ Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
¹⁶ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. sisichen@shsmu.edu.cn.
¹⁷ Precision Research Center for Refractory Diseases, Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China. sisichen@shsmu.edu.cn.
¹⁸ Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. yan.liu@northwestern.edu.
¹⁹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. yan.liu@northwestern.edu.
²⁰ Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, 60611, USA. yan.liu@northwestern.edu.

PMID: 39562720
DOI: 10.1038/s41375-024-02462-w

Abstract

Polycomb group (PcG) proteins play important roles in hematopoietic stem cell (HSC) self-renewal. Mel18 and Bmi1 are homologs of the PCGF subunit within the Polycomb repressive complex 1 (PRC1). Bmi1 (PCGF4) enhances HSC self-renewal and promotes terminal differentiation. However, the role of Mel18 (PCGF2) in hematopoiesis is not fully understood and how Mel18 regulates gene transcription in HSCs remains elusive. We found that acute deletion of Mel18 in the hematopoietic compartment significantly increased the frequency of functional HSCs in the bone marrow. Furthermore, we demonstrate that Mel18 inhibits HSC self-renewal and proliferation. RNA-seq studies revealed that HSC self-renewal and proliferation gene signatures are enriched in Mel18^-/- hematopoietic stem and progenitors (HSPCs) compared to Mel18^+/+ HSPCs. Notably, ATAC-seq revealed increased chromatin accessibility at genes important for HSC self-renewal, whereas CUT&RUN showed decreased enrichment of H2AK119ub1 at genes important for proliferation, leading to increased expression of both Hoxb4 and Cdk4 in Mel18^-/- HSPCs. Thus, we demonstrate that Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of genes important for HSC self-renewal and proliferation.