Lymphoid-affiliated genes are associated with active histone modifications in human hematopoietic stem cells
Lymphoid-affiliated genes are associated with active histone modifications in human hematopoietic stem cells
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DOI：
10.1182/blood-2008-02-140806
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发表时间：
2008-10-01
期刊：
影响因子：
20.3
通讯作者：
Goodhardt, Michele
中科院分区：
文献类型：
--
作者：
Maes, Jerome;Maleszewska, Marta;Goodhardt, Michele
要解决的作用，染色质结构的造血干细胞（HSC）的多谱系潜力和承诺的淋巴谱系的建立，我们分析了组蛋白修饰在一个小组的淋巴和骨髓相关基因的多能和谱系定向造血细胞分离自人脐带血。我们的研究结果表明，许多B-和T-淋巴基因，虽然在HSC沉默，与乙酰化组蛋白H3和H4。我们还检测到组蛋白H3赖氨酸4甲基化，但在这些位点没有抑制性赖氨酸9或27甲基化标记，表明开放的染色质结构。有趣的是，在B特异性基因座处H3赖氨酸4二甲基化至三甲基化的相对水平在多能CD 34（+）CD 38（lo）祖细胞中较高，并且随着它们在B谱系细胞中变得活跃转录而降低。在体外，CD 34（+）细胞向红系、粒细胞和T细胞谱系的分化导致非谱系相关基因组蛋白乙酰化的丧失。这项研究提供的证据表明，组蛋白修饰参与染色质去凝聚已经在原代人HSC的淋巴特异性基因，支持的想法，这些基因是“启动”的谱系承诺之前的表达。这种允许的染色质结构随着干细胞分化而逐渐丧失。
To address the role of chromatin structure in the establishment of hematopoietic stem cell (HSC) multilineage potential and commitment to the lymphoid lineage, we have analyzed histone modifications at a panel of lymphoid- and myeloid-affiliated genes in multipotent and lineage-committed hematopoietic cells isolated from human cord blood. Our results show that many B- and T-lymphoid genes, although silent in HSCs, are associated with acetylated histones H3 and H4. We also detected histone H3 lysine 4 methylation but not repressive lysine 9 or 27 methylation marks at these loci, indicative of an open chromatin structure. Interestingly, the relative level of H3 lysine 4 dimethylation to trimethylation at B-specific loci was high in multipotent CD34(+)CD38(lo) progenitors and decreased as they become actively transcribed in B-lineage cells. In vitro differentiation of CD34(+) cells toward the erythroid, granulocyte, and T-cell lineages resulted in a loss of histone acetylation at nonlineage-associated genes. This study provides evidence that histone modifications involved in chromatin decondensation are already in place at lymphoid-specific genes in primary human HSCs, supporting the idea that these genes are "primed" for expression before lineage commitment. This permissive chromatin structure is progressively lost as the stem cell differentiates.