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巨核细胞谱系发育受蛋白质乙酰化修饰的调控。

Megakaryocyte lineage development is controlled by modulation of protein acetylation.

机构信息

Center for Molecular Medicine and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands.

Division of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands.

出版信息

PLoS One. 2018 Apr 26;13(4):e0196400. doi: 10.1371/journal.pone.0196400. eCollection 2018.

DOI:10.1371/journal.pone.0196400
PMID:29698469
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5919413/
Abstract

Treatment with lysine deacetylase inhibitors (KDACi) for haematological malignancies, is accompanied by haematological side effects including thrombocytopenia, suggesting that modulation of protein acetylation affects normal myeloid development, and specifically megakaryocyte development. In the current study, utilising ex-vivo differentiation of human CD34+ haematopoietic progenitor cells, we investigated the effects of two functionally distinct KDACi, valproic acid (VPA), and nicotinamide (NAM), on megakaryocyte differentiation, and lineage choice decisions. Treatment with VPA increased the number of megakaryocyte/erythroid progenitors (MEP), accompanied by inhibition of megakaryocyte differentiation, whereas treatment with NAM accelerated megakaryocyte development, and stimulated polyploidisation. Treatment with both KDACi resulted in no significant effects on erythrocyte differentiation, suggesting that the effects of KDACi primarily affect megakaryocyte lineage development. H3K27Ac ChIP-sequencing analysis revealed that genes involved in myeloid development, as well as megakaryocyte/erythroid (ME)-lineage differentiation are uniquely modulated by specific KDACi treatment. Taken together, our data reveal distinct effects of specific KDACi on megakaryocyte development, and ME-lineage decisions, which can be partially explained by direct effects on promoter acetylation of genes involved in myeloid differentiation.

摘要

治疗血液系统恶性肿瘤的赖氨酸去乙酰化酶抑制剂 (KDACi) 伴随着血液学副作用，包括血小板减少症，这表明蛋白质乙酰化的调节会影响正常的髓系发育，特别是巨核细胞的发育。在本研究中，我们利用人 CD34+造血祖细胞的体外分化，研究了两种功能不同的 KDACi（丙戊酸 (VPA) 和烟酰胺 (NAM)）对巨核细胞分化和谱系选择决定的影响。VPA 处理增加了巨核细胞/红细胞祖细胞 (MEP) 的数量，同时抑制巨核细胞分化，而 NAM 处理加速了巨核细胞的发育，并刺激了多倍体化。两种 KDACi 的处理对红细胞分化均无显著影响，这表明 KDACi 的作用主要影响巨核细胞谱系的发育。H3K27Ac ChIP-seq 分析表明，参与髓系发育以及巨核细胞/红细胞 (ME) 谱系分化的基因被特定 KDACi 处理特异性地调节。总之，我们的数据揭示了特定 KDACi 对巨核细胞发育和 ME 谱系决定的独特影响，这可以部分解释为对参与髓系分化的基因启动子乙酰化的直接影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/006b5e9be834/pone.0196400.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/44c041606795/pone.0196400.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/0abb73a938a2/pone.0196400.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/96be8c0fce81/pone.0196400.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/96776d7b8ebd/pone.0196400.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/006b5e9be834/pone.0196400.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/44c041606795/pone.0196400.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/0abb73a938a2/pone.0196400.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/96be8c0fce81/pone.0196400.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/96776d7b8ebd/pone.0196400.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62d0/5919413/006b5e9be834/pone.0196400.g005.jpg

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