诱导细胞身份逆转过程中抑制性表观遗传修饰的协调去除。
Coordinated removal of repressive epigenetic modifications during induced reversal of cell identity.
机构信息
Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA.
Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA.
出版信息
EMBO J. 2019 Nov 15;38(22):e101681. doi: 10.15252/embj.2019101681. Epub 2019 Oct 4.
Abstract
Epigenetic modifications operate in concert to maintain cell identity, yet how these interconnected networks suppress alternative cell fates remains unknown. Here, we uncover a link between the removal of repressive histone H3K9 methylation and DNA methylation during the reprogramming of somatic cells to pluripotency. The H3K9me2 demethylase, Kdm3b, transcriptionally controls DNA hydroxymethylase Tet1 expression. Unexpectedly, in the absence of Kdm3b, loci that must be DNA demethylated are trapped in an intermediate hydroxymethylated (5hmC) state and do not resolve to unmethylated cytosine. Ectopic 5hmC trapping precludes the chromatin association of master pluripotency factor, POU5F1, and pluripotent gene activation. Increased Tet1 expression is important for the later intermediates of the reprogramming process. Taken together, coordinated removal of distinct chromatin modifications appears to be an important mechanism for altering cell identity.
摘要
表观遗传修饰协同作用以维持细胞身份，然而这些相互关联的网络如何抑制替代细胞命运仍然未知。在这里，我们揭示了体细胞重编程为多能性过程中去除抑制性组蛋白 H3K9 甲基化和 DNA 甲基化之间的联系。H3K9me2 去甲基酶 Kdm3b 转录控制 DNA 羟甲基酶 Tet1 的表达。出乎意料的是，在没有 Kdm3b 的情况下，必须进行 DNA 去甲基化的基因座被滞留在中间羟甲基化（5hmC）状态，并且不能解析为未甲基化的胞嘧啶。异位 5hmC 捕获阻止了主多能因子 POU5F1 和多能基因激活的染色质关联。Tet1 表达的增加对于重编程过程的后期中间阶段很重要。总之，协调去除不同的染色质修饰似乎是改变细胞身份的重要机制。
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