CTR9/PAF1c regulates molecular lineage identity, histone H3K36 trimethylation and genomic imprinting during preimplantation development.
CTR9/PAF1c regulates molecular lineage identity, histone H3K36 trimethylation and genomic imprinting during preimplantation development.
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DOI：
10.1016/j.ydbio.2013.09.005
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发表时间：
2013-11-01
影响因子：
2.7
通讯作者：
Mager J
中科院分区：
文献类型：
--
作者：
Zhang K;Haversat JM;Mager J
全基因组表观遗传重编程是成功的胚胎植入前发育所必需的。不适当或缺陷的染色质调控可导致谱系规范缺陷和基因组印迹的丢失，损害正常发育。在这里，我们报道了RNA聚合酶II相关因子的两个成员，同源（酿酒酵母）复合物（PAF1复合物）组分，Ctr9和Rtf1，在哺乳动物着床前发育过程中是必需的。我们证明，在囊胚阶段，缺乏ctr9的胚胎不能正确地指定谱系。在Ctr9敲低的胚胎中，一些谱系特异性因子的表达明显降低，包括Eomes、Elf5和Sox2，而其他一些基因的表达则不适当（Oct4、Nanog、Gata6、Fgf4和Sox17）。我们还发现一些印迹基因（Mest, Peg3， Snrpn和Meg3）异常表达，尽管等位基因特异性DNA甲基化没有改变。我们记录了在ctr9缺陷胚胎中组蛋白H3赖氨酸36三甲基化（H3K36me3）的缺失，并证实敲低Setd2或Rtf1都会导致相似的表型。这些发现表明，PAF1复合体是哺乳动物发育所必需的，可能通过调控H3K36me3，并表明PAF1复合体在酵母菌到哺乳动物体内的功能保存。
Genome-wide epigenetic reprogramming is required for successful preimplantation development. Inappropriate or deficient chromatin regulation can result in defective lineage specification and loss of genomic imprinting, compromising normal development. Here we report that two members of the RNA polymerase II associated factor, homolog (Saccharomyces cerevisiae) complex (PAF1 complex) components, Ctr9 and Rtf1, are required during mammalian preimplantation development. We demonstrate that Ctr9-deficient embryos fail to correctly specify lineages at the blastocyst stage. Expression of some lineage specific factors is markedly reduced in Ctr9 knockdown embryos, including Eomes, Elf5 and Sox2, while others are inappropriately expressed (Oct4, Nanog, Gata6, Fgf4 and Sox17). We also show that several imprinted genes (Mest, Peg3, Snrpn and Meg3) are aberrantly expressed although allele specific DNA methylation is not altered. We document a loss of histone H3 lysine 36 trimethylation (H3K36me3) in Ctr9-deficient embryos and confirm that knockdown of either Setd2 or Rtf1 results in similar phenotypes. These findings show that the PAF1 complex is required for mammalian development, likely through regulation of H3K36me3, and indicate functional conservation of the PAF1 complex from yeast to mammals in vivo.