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多梳抑制复合物 1.1 协调稳态和应急髓系造血。

Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis.

机构信息

Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

出版信息

Elife. 2023 Jun 2;12:e83004. doi: 10.7554/eLife.83004.

DOI:10.7554/eLife.83004
PMID:37266576
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10287155/
Abstract

Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B, and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here we show that PRC1.1 serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state hematopoiesis by restricting C/EBPα-dependent precocious myeloid differentiation of HSPCs and the HOXA9- and β-catenin-driven self-renewing network in myeloid progenitors. Upon regeneration, PRC1.1 is transiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover, constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as a novel critical regulator of emergency myelopoiesis, dysregulation of which leads to myeloid transformation.

摘要

多梳抑制复合物 (PRC) 1 通过介导组蛋白 H2A 赖氨酸 119 的单泛素化来调节干细胞命运。虽然经典的 PRC1 对于造血干细胞和祖细胞 (HSPC) 的维持至关重要，但非经典的 PRC1 在造血中的作用仍不清楚。PRC1.1 是一种非典型的 PRC1，由 PCGF1、RING1B、KDM2B 和 BCOR 组成。我们最近表明，PCGF1 或 BCOR 的缺失导致的 PRC1.1 不足会引起偏粒细胞性造血，并促进造血细胞在小鼠中的转化。在这里，我们表明 PRC1.1 作为一种表观遗传开关，协调稳态和应急造血。PRC1.1 通过限制 HSPC 中 C/EBPα 依赖性过早髓样分化和髓系祖细胞中 HOXA9 和 β-连环蛋白驱动的自我更新网络，维持稳态造血的平衡输出。在再生过程中，PRC1.1 被短暂抑制以促进粒细胞-巨噬细胞祖细胞 (GMP) 集落的形成，从而促进应急髓样生成。此外，PRC1.1 的组成性失活导致 GMP 的不受控制的扩增并最终导致转化。总之，我们的结果将 PRC1.1 定义为应急髓样生成的新型关键调节剂，其失调会导致髓样转化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/24af4b14b4f0/elife-83004-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/917b6711a16d/elife-83004-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/3bb163eafb66/elife-83004-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/dc1e696be091/elife-83004-fig1-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/bc2002a9ce87/elife-83004-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/24af4b14b4f0/elife-83004-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/917b6711a16d/elife-83004-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/3bb163eafb66/elife-83004-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/dc1e696be091/elife-83004-fig1-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/bc2002a9ce87/elife-83004-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad9e/10287155/24af4b14b4f0/elife-83004-fig3.jpg

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