Nuclear and chromatin reorganization in the MHC-Oct3/4 locus at developmental phases of embryonic stem cell differentiation
Nuclear and chromatin reorganization in the MHC-Oct3/4 locus at developmental phases of embryonic stem cell differentiation
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DOI：
10.1016/j.ydbio.2006.04.450
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发表时间：
2006-10-15
影响因子：
2.7
通讯作者：
Nakao, Mitsuyoshi
中科院分区：
文献类型：
--
作者：
Aoto, Takahiro;Saitoh, Noriko;Nakao, Mitsuyoshi
表观遗传基因控制参与发育机制。小鼠胚胎干细胞（ESC）程序性分化过程中核和染色质事件的协同作用知之甚少。为了解决这个问题，Oct 3/4阳性ESC和分化后代，Sox 1阳性神经前体细胞（NPC）和有丝分裂后神经元（PMN），使用阶段选择的培养系统分离。我们首先考察了各个阶段的全球核组织。染色中心先存在于ESC中，在NPC中分散，在PMN中整合成大的异染色质灶，而PML小体的形成在神经分化中明显减少。我们接下来关注基因密集的MHC-Oct 3/4区域。Oct 3/4基因在ESC中优先在PML小体附近表达，在NPC和PMN中在没有染色中心缔合的情况下被抑制。NPC中的历史脱乙酰化、组蛋白H3（H3 K4）的赖氨酸4的脱甲基化、H3 K27的三甲基化和PMN中的CpG甲基化靶向于该区域内的Oct 3/4启动子。有趣的是，二甲基H3 K4标记存在于NPC和ESC的Oct 3/4启动子中。这些研究结果提供了深入了解全球核重组和常染色质基因沉默的分化，通过时空顺序的表观遗传控制的分子基础。(c)2006年爱思唯尔公司All rights reserved.
Epigenetic gene control is involved in mechanisms of development. Little is known about the cooperation of nuclear and chromatin events in programmed differentiation from mouse embryonic stem cells (ESC). To address this, Oct3/4-positive ESC and differentiated progenies, Sox1-positive neural precursor cells (NPC) and post-mitotic neurons (PMN), were isolated using a stage-selected culture system. We first investigated global nuclear organization at the each stage. Chromocenter preexists in ESC, disperses in NPC and becomes integrated into large heterochromatic foci in PMN, while the formation of PML bodies markedly decreases in neural differentiation. We next focused on the gene-dense MHC-Oct3/4 region. Oct3/4 gene is expressed preferentially adjacent to PML bodies in ESC and are repressed in the absence of chromocenter association in NPC and PMN. Historic deacetylation in NPC, demethylation of lysine 4 of histone H3 (H3K4), tri-methylation of H3K27, and CpG methylation in PMN are targeted for the Oct3/4 promoter within the region. Interestingly, di-methyl H3K4 mark is present in Oct3/4 promoter in NPC as well as ESC. These findings provide insights into the molecular basis of global nuclear reorganization and euchromatic gene silencing in differentiation through the spatiotemporal order of epigenetic controls. (c) 2006 Elsevier Inc. All rights reserved.