Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation.
Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation.
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DOI：
10.7554/elife.00633
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发表时间：
2013-06-18
期刊：
影响因子：
7.7
通讯作者：
Orkin SH
中科院分区：
文献类型：
--
作者：
Kerenyi MA;Shao Z;Hsu YJ;Guo G;Luc S;O'Brien K;Fujiwara Y;Peng C;Nguyen M;Orkin SH
在这里，我们描述了赖氨酸特异性去甲基化酶1（Lsd 1/KDM 1a），它去甲基化组蛋白H3的Lys 4或Lys 9（H3 K4/K9），是一个不可或缺的造血分化的表观遗传总督。综合基因组分析，结合Lsd 1的全局占用，其底物H3 K4单甲基化和二甲基化的全基因组分析，以及基因表达谱，揭示了Lsd 1抑制造血干细胞和祖细胞（HSPC）基因表达程序在造血分化。我们发现Lsd 1作用于转录起始位点以及增强子区域。Lsd 1的缺失与HSPC基因上H3 K4 me 1和H3 K4 me 2甲基化增加和基因去阻遏相关。未能完全沉默HSPC基因损害造血干细胞以及成熟血细胞谱系的分化。总的来说，我们的数据表明，Lsd 1介导的干细胞和祖细胞基因的增强子和启动子活性的同时抑制是适当的造血成熟所需的关键表观遗传机制。http://dx.doi.org/10.7554/eLife.00633.001我们的血液含有许多不同类型的细胞。红细胞携带氧气到身体各处，而白色细胞是我们免疫系统的关键部分。所有这些不同类型的血细胞都来自我们骨髓中的特殊细胞，称为造血干细胞。干细胞变成的血细胞类型取决于干细胞中表达为蛋白质的基因。基因表达可以通过多种方式进行控制，包括影响基因表达而不改变DNA中碱基序列的表观遗传过程。例如，DNA包裹在组蛋白周围，在这些蛋白质中添加甲基，这一过程称为组蛋白甲基化，可以增加基因的表达，而去除甲基（去甲基化）可以抑制基因表达。赖氨酸特异性去甲基化酶1（Lsd 1）是一种已知介导组蛋白上赖氨酸氨基酸去甲基化的酶。Lsd 1在胚胎干细胞中的作用已被广泛研究，已知Lsd 1编码基因的缺失会导致小鼠胚胎死亡。然而，很少有人知道它在哺乳动物发育后期的作用。在这里，Kerenyi等人使用新的遗传工具在不同的发育阶段敲除Lsd 1基因，以研究其对新血细胞形成的影响。他们发现Lsd 1是造血干细胞成功分化为不同类型血细胞所必需的，敲除Lsd 1会导致白色和红细胞的严重损失。此外，它们表明Lsd 1的缺乏在发育的早期和后期都会引起问题。Kerenyi等人继续证明Lsd 1调节与造血干细胞相关的各种基因的启动子和增强子的活性。他们还表明，敲除Lsd 1基因会导致这些基因的沉默受损，并且这些基因的不完全表达与血细胞的成熟不相容。Lsd 1最近被提议作为治疗白血病和其他血液疾病的潜在靶点。然而，Lsd 1功能丧失在血细胞发育的早期和后期都有不良影响，这一事实表明，靶向Lsd 1的药物研究不应该开始，直到可以确定合适的给药时间窗。DOI：http://dx.doi.org/10.7554/eLife.00633.002网站
Here, we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which demethylates histone H3 on Lys4 or Lys9 (H3K4/K9), is an indispensible epigenetic governor of hematopoietic differentiation. Integrative genomic analysis, combining global occupancy of Lsd1, genome-wide analysis of its substrates H3K4 monomethylation and dimethylation, and gene expression profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell (HSPC) gene expression programs during hematopoietic differentiation. We found that Lsd1 acts at transcription start sites, as well as enhancer regions. Loss of Lsd1 was associated with increased H3K4me1 and H3K4me2 methylation on HSPC genes and gene derepression. Failure to fully silence HSPC genes compromised differentiation of hematopoietic stem cells as well as mature blood cell lineages. Collectively, our data indicate that Lsd1-mediated concurrent repression of enhancer and promoter activity of stem and progenitor cell genes is a pivotal epigenetic mechanism required for proper hematopoietic maturation. DOI: http://dx.doi.org/10.7554/eLife.00633.001 Our blood contains many different types of cells. Red blood cells carry oxygen around the body, whereas white blood cells are a key part of our immune system. All these different types of blood cells are derived from special cells in our bone marrow called hematopoietic stem cells. The type of blood cell that the stem cell becomes depends on the genes that are expressed as proteins in that stem cell. Gene expression can be controlled in a number of ways, including epigenetic process that influence the expression of genes without altering the underlying sequence of bases in the DNA. For example, DNA is wrapped around histone proteins and the addition of a methyl group to these proteins, a process known as histone methylation, can increase the expression of a gene, whereas the removal of a methyl group (demethylation) can repress gene expression. Lysine-specific demethylase 1 (Lsd1) is an enzyme that is known to mediate the demethylation of lysine amino acids on histone proteins. The role of Lsd1 in embryonic stem cells has been widely studied, and deletion of the gene that codes for Lsd1 is known to result in the death of mice embryos. However, very little is known about its roles in the later stages of mammalian development. Here, Kerenyi et al. use new genetic tools to knock out the gene for Lsd1 at different stages of development in order to examine its impact on the formation of new blood cells. They find that Lsd1 is required for the successful differentiation of hematopoietic stem cells into different types of blood cells, and that knocking out Lsd1 results in a severe loss of white and red blood cells. Moreover, they show that the lack of Lsd1 causes problems during both the early and later stages of development. Kerenyi et al. go on to demonstrate that Lsd1 regulates the activity of promoters and enhancers of various genes associated with hematopoietic stem cells. They also show that knocking out the Lsd1 gene results in impaired silencing of these genes, and that the incomplete expression of these genes is not compatible with the maturation of blood cells. Lsd1 has recently been proposed as the potential target for the treatment of leukemia and other blood disorders. However, the fact that a loss of Lsd1 function has adverse effects during both the early and later stages of blood cell development suggests that research into drugs that target Lsd1 should not begin until a suitable time window for the administration of such drugs can be identified. DOI: http://dx.doi.org/10.7554/eLife.00633.002