CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells.
CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells.
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DOI：
10.1371/journal.pgen.0020181
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发表时间：
2006-11-03
期刊：
影响因子：
4.5
通讯作者：
Gerard, Matthieu
中科院分区：
文献类型：
--
作者：
Houlard, Martin;Berlivet, Soizik;Probst, Aline V.;Quivy, Jean-Pierre;Hery, Patrick;Almouzni, Genevieve;Gerard, Matthieu
在哺乳动物发育过程中，染色质动态和表观遗传标记对于基因组重编程非常重要。最近的数据表明，染色质组装机制在这一过程中发挥了重要作用。为了分析染色质组装因子1(CAF-1)在植入前发育过程中的作用，我们建立了一个携带其大亚基p150CAF-1编码基因的靶向突变的小鼠系。纯合子突变体中p150CAF-1的缺失会导致16-细胞期的发育停滞。这些胚胎中缺乏p150CAF-1，导致构成异染色质的核组织发生严重变化。我们提供的证据表明，在野生型胚胎中，异染色质结构域在双细胞期和囊胚期之间被广泛重组。在p150CAF-1突变的16-细胞期胚胎中，异染色质结构的改变与2-4细胞期野生型胚胎的异染色质结构相似，提示CAF-1在着床前发育过程中异染色质的成熟需要CAF-1。在胚胎干细胞中，使用RNA干扰耗尽p150CAF-1会导致中心周围异染色质结构域的错误定位、聚集和解聚。此外，CAF-1在这些细胞中的丢失导致了在着丝粒周围异染色质水平上的表观遗传组蛋白甲基化标记的改变。在p150CAF-1缺失的小鼠胚胎成纤维细胞中没有发现这些异染色质的变化，这表明在多能胚胎细胞中，异染色质的组织特别需要CAF-1。我们的发现强调了染色质组装机制在控制早期胚胎和胚胎干细胞基因组的空间组织和表观遗传标记中的作用。染色质是我们遗传信息的支撑。它由许多被称为核小体的重复单位组成，在核小体中，DNA包裹着组蛋白的核心。核小体的组成和生化性质的改变在基因组功能的调节中起着重要作用。这种修饰被称为“表观遗传”，当它们在细胞分裂中遗传，并在DNA提供的遗传信息之外，还向染色质提供新的信息。人们通常认为，在基因组复制过程中，基本的染色质组装机制会建立起天真的核小体，在接下来的一步中，核小体被一系列酶选择性地修饰，以获得表观遗传信息。在这里，作者研究了碱性染色质组装因子(CAF-1)在小鼠胚胎干细胞和早期胚胎中的作用。令人惊讶的是，他们发现CAF-1将表观遗传信息传递给特定的基因组区域。此外，这项研究还揭示了CAF-1对于细胞核中染色体的正确空间组织是必需的。这一新知识可能有助于更好地理解染色质在维持胚胎干细胞特性和可塑性中的作用。
During mammalian development, chromatin dynamics and epigenetic marking are important for genome reprogramming. Recent data suggest an important role for the chromatin assembly machinery in this process. To analyze the role of chromatin assembly factor 1 (CAF-1) during pre-implantation development, we generated a mouse line carrying a targeted mutation in the gene encoding its large subunit, p150CAF-1. Loss of p150CAF-1 in homozygous mutants leads to developmental arrest at the 16-cell stage. Absence of p150CAF-1 in these embryos results in severe alterations in the nuclear organization of constitutive heterochromatin. We provide evidence that in wild-type embryos, heterochromatin domains are extensively reorganized between the two-cell and blastocyst stages. In p150CAF-1 mutant 16-cell stage embryos, the altered organization of heterochromatin displays similarities to the structure of heterochromatin in two- to four-cell stage wild-type embryos, suggesting that CAF-1 is required for the maturation of heterochromatin during preimplantation development. In embryonic stem cells, depletion of p150CAF-1 using RNA interference results in the mislocalization, loss of clustering, and decondensation of pericentric heterochromatin domains. Furthermore, loss of CAF-1 in these cells results in the alteration of epigenetic histone methylation marks at the level of pericentric heterochromatin. These alterations of heterochromatin are not found in p150CAF-1-depleted mouse embryonic fibroblasts, which are cells that are already lineage committed, suggesting that CAF-1 is specifically required for heterochromatin organization in pluripotent embryonic cells. Our findings underline the role of the chromatin assembly machinery in controlling the spatial organization and epigenetic marking of the genome in early embryos and embryonic stem cells. Chromatin is the support of our genetic information. It is composed of numerous repeated units called nucleosomes, in which DNA wraps around a core of histone proteins. Modifications in the composition and biochemical properties of nucleosomes play major roles in the regulation of genome function. Such modifications are termed “epigenetic” when they are inherited across cell divisions and confer new information to chromatin, in addition to the genetic information provided by DNA. It is usually believed that during genome replication, the basic chromatin assembly machinery builds up “naïve” nucleosomes, and, in a subsequent step, nucleosomes are selectively modified by a series of enzymes to acquire epigenetic information. Here, the authors studied the role of a basic chromatin assembly factor (CAF-1) in mouse embryonic stem cells and early embryos. Surprisingly, they show that CAF-1 confers epigenetic information to specific genomic regions. In addition, this study revealed that CAF-1 is required for the proper spatial organization of chromosomes in the nucleus. This new knowledge may contribute to better understanding the role of chromatin in the maintenance of embryonic stem cell identity and plasticity.
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DOI：
10.1073/pnas.211322798
发表时间：
2001-10-09
影响因子：
11.1
作者：
Gilbert, N;Allan, J
通讯作者：
Allan, J
影响因子：
5.3
作者：
Buchou, T;Vernet, M;Boldyreff, B
通讯作者：
Boldyreff, B
影响因子：
11.4
作者：
Martens, JHA;O'Sullivan, RJ;Jenuwein, T
通讯作者：
Jenuwein, T
影响因子：
64.8
作者：
CHAPMAN, V;FORRESTER, L;ROSSANT, J
通讯作者：
ROSSANT, J
DOI：
10.1073/pnas.1635158100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Hoek, M;Stillman, B
通讯作者：
Stillman, B