TY - JOUR
T1 - Polycomb group protein Mel18 inhibits hematopoietic stem cell self-renewal through repressing the transcription of self-renewal and proliferation genes
AU - Cai, Wenjie
AU - Liu, Xicheng
AU - Barajas, Sergio
AU - Xiao, Shiyu
AU - Vemula, Sasidhar
AU - Chen, Hongxia
AU - Yang, Yuxia
AU - Bochers, Christopher
AU - Henley, Danielle
AU - Liu, Sheng
AU - Jia, Yuzhi
AU - Hong, Michelle
AU - Mays, Tiffany M.
AU - Capitano, Maegan L.
AU - Liu, Huiping
AU - Ji, Peng
AU - Gao, Zhonghua
AU - Pasini, Diego
AU - Wan, Jun
AU - Yue, Feng
AU - Platanias, Leonidas C.
AU - Xi, Rongwen
AU - Chen, Sisi
AU - Liu, Yan
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
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U2 - 10.1038/s41375-024-02462-w
DO - 10.1038/s41375-024-02462-w
M3 - Article
C2 - 39562720
AN - SCOPUS:85209630241
SN - 0887-6924
JO - Leukemia
JF - Leukemia
ER -