Geminin restrains mesendodermal fate acquisition of embryonic stem cells and is associated with antagonism of Wnt signaling and enhanced polycomb-mediated repression.
Geminin restrains mesendodermal fate acquisition of embryonic stem cells and is associated with antagonism of Wnt signaling and enhanced polycomb-mediated repression.
复制标题
Geminin 抑制胚胎干细胞的中内胚层命运获得，并与 Wnt 信号传导的拮抗和增强的多梳介导的抑制有关。
DOI：
10.1002/stem.1410
复制
发表时间：
2013-08
期刊：
影响因子：
5.2
通讯作者：
Kroll, Kristen L.
中科院分区：
文献类型：
--
作者：
Caronna, Elizabeth A.;Patterson, Ethan S.;Hummert, Pamela M.;Kroll, Kristen L.
胚胎细胞利用生长因子信号传导和细胞内在转录和表观遗传调控来获得早期细胞命运。人们对整合这些线索的潜在机制知之甚少。在这里，我们研究了 Geminin（一种与转录因子和表观遗传调控复合物相互作用的核蛋白）在小鼠胚胎干细胞命运获得过程中的作用。为了确定 Geminin 在中内胚层形成（胚胎原肠胚形成过程中发生的过程）中的作用，我们在分化小鼠胚胎干细胞的体外模型中选择性过度表达或敲低 Geminin。我们发现 Geminin 拮抗中内胚层命运的获得，而这些细胞反而维持与胚胎干细胞多能性相关的基因表达升高。在中内胚层命运获得过程中，Geminin 敲低会促进 Wnt 信号传导，而 Bmp、Fgf 和 Nodal 信号传导不受影响。此外，我们发现 Geminin 有助于抑制由 Polycomb 阻遏物复合体调节的中内胚层基因。 Geminin 直接结合其中几个基因，而中内胚层细胞中的 Geminin 敲低会减少这些位点上的 Polycomb 阻遏复合物的占据，并增加组蛋白 H3 赖氨酸 4 的三甲基化，这与活性基因表达相关。总之，这些结果表明需要 Geminin 来抑制早期胚胎细胞的中内胚层命运获得，并且这与 Wnt 信号传导的减少和中内胚层基因中 Polycomb 阻遏物复合物保留的增强有关。
Embryonic cells utilize both growth factor signaling and cell intrinsic transcriptional and epigenetic regulation to acquire early cell fates. Underlying mechanisms that integrate these cues are poorly understood. Here we investigated the role of Geminin, a nucleoprotein that interacts with both transcription factors and epigenetic regulatory complexes, during fate acquisition of mouse embryonic stem cells. In order to determine Geminin’s role in mesendoderm formation, a process which occurs during embryonic gastrulation, we selectively over-expressed or knocked down Geminin in an in vitro model of differentiating mouse embryonic stem cells. We found that Geminin antagonizes mesendodermal fate acquisition, while these cells instead maintain elevated expression of genes associated with pluripotency of embryonic stem cells. During mesendodermal fate acquisition, Geminin knockdown promotes Wnt signaling, while Bmp, Fgf, and Nodal signaling are not affected. Moreover, we showed that Geminin facilitates the repression of mesendodermal genes that are regulated by the Polycomb repressor complex. Geminin directly binds several of these genes, while Geminin knockdown in mesendodermal cells reduces Polycomb repressor complex occupancy at these loci and increases trimethylation of histone H3 lysine 4, which correlates with active gene expression. Together, these results indicate that Geminin is required to restrain mesendodermal fate acquisition of early embryonic cells and that this is associated with both decreased Wnt signaling and enhanced Polycomb repressor complex retention at mesendodermal genes.
登录
查看更多内容
影响因子：
4.8
作者：
Bakre, Manjiri Manohar;Hoi, Aina;Stanton, Lawrence W.
通讯作者：
Stanton, Lawrence W.
影响因子：
64.8
作者：
Del Bene, F;Tessmar-Raible, K;Wittbrodt, J
通讯作者：
Wittbrodt, J
DOI：
10.1073/pnas.151258098
发表时间：
2001-07-17
影响因子：
11.1
作者：
Galceran, J;Hsu, SC;Grosschedl, R
通讯作者：
Grosschedl, R
影响因子：
11.4
作者：
Izzi, Luisa;Silvestri, Cristoforo;Attisano, Liliana
通讯作者：
Attisano, Liliana
DOI：
10.1242/dev.014357
发表时间：
2008-02
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Arnold SJ;Hofmann UK;Bikoff EK;Robertson EJ
通讯作者：
Robertson EJ