Attema Joanne L, Papathanasiou Peter, Forsberg E Camilla, Xu Jian, Smale Stephen T, Weissman Irving L
Institute of Stem Cell Biology and Regenerative Medicine, Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12371-6. doi: 10.1073/pnas.0704468104. Epub 2007 Jul 18.
Hematopoietic stem cells (HSC) produce all blood cell lineages by virtue of their capacity to self-renew and differentiate into progenitors with decreasing cellular potential. Recent studies suggest that epigenetic mechanisms play an important role in controlling stem cell potency and cell fate decisions. To investigate this hypothesis in HSC, we have modified the conventional chromatin immunoprecipitation assay allowing for the analysis of 50,000 prospectively purified stem and progenitor cells. Together with bisulfite sequencing analysis, we found that methylated H3K4 and AcH3 and unmethylated CpG dinucleotides colocalize across defined regulatory regions of lineage-affiliated genes in HSC. These active epigenetic histone modifications either accumulated or were replaced by increased DNA methylation and H3K27 trimethylation in committed progenitors consistent with gene expression. We also observed bivalent histone modifications at a lymphoid-affiliated gene in HSC and downstream transit-amplifying progenitors. Together, these data support a model in which epigenetic modifications serve as an important mechanism to control HSC multipotency.
造血干细胞（HSC）凭借其自我更新能力以及分化为细胞潜能逐渐降低的祖细胞的能力，产生所有血细胞谱系。最近的研究表明，表观遗传机制在控制干细胞潜能和细胞命运决定中发挥着重要作用。为了在造血干细胞中研究这一假设，我们改进了传统的染色质免疫沉淀试验，以便能够分析50000个经前瞻性纯化的干细胞和祖细胞。结合亚硫酸氢盐测序分析，我们发现甲基化的H3K4和乙酰化的H3以及未甲基化的CpG二核苷酸在造血干细胞中跨谱系相关基因的特定调控区域共定位。这些活跃的表观遗传组蛋白修饰在定向祖细胞中要么积累，要么被与基因表达一致的DNA甲基化增加和H3K27三甲基化所取代。我们还在造血干细胞和下游过渡扩增祖细胞中的一个淋巴系相关基因上观察到了二价组蛋白修饰。总之，这些数据支持了一个模型，其中表观遗传修饰是控制造血干细胞多能性的重要机制。
