Impaired placental trophoblast lineage differentiation in Alkbh1-/- mice
Impaired placental trophoblast lineage differentiation in Alkbh1-/- mice
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DOI：
10.1002/dvdy.21418
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发表时间：
2008-02-01
影响因子：
2.5
通讯作者：
Lipkin, Steven M.
中科院分区：
文献类型：
--
作者：
Pan, Zishu;Sikandar, Shaheen;Lipkin, Steven M.
自 1983 年以来，人们对大肠杆菌 AlkB 进行了深入研究，但其哺乳动物同源物 Alkbh1 的体内作用尚不清楚。因此，我们为 Alkbh1 创建了无效小鼠。 Alkbh1 mRNA 在发育胎盘的滋养层谱系中表达水平最高。 Alkbh1-/- 胎盘降低了分化滋养层标记物（包括 Tpbp、Gcm1 和 Pl-1）的表达，并增加了滋养层干细胞标记物 Eomes 的表达。 Alkbh1 定位于核常染色质，并与 Mrj 强烈相互作用，Mrj 是一种重要的胎盘基因，通过招募 11 类组蛋白脱乙酰酶 (HDAC) 介导基因抑制。竞争实验表明 Alkbh1 和 HDAC4 与 Mrj 的结合是相互排斥的，这会导致 HDAC 活性降低和靶基因表达增加。我们的研究表明 Alkbh1 在胎盘滋养层谱系分化中发挥重要作用并参与转录调控机制。
E. coli AlkB has been intensively studied since 1983, but the in vivo roles of its mammalian homologue Alkbh1 are unknown. We, therefore, created null mice for Alkbh1. Alkbh1 mRNA is expressed at highest levels in the trophoblast lineages of the developing placenta. Alkbh1-/- placentas have decreased expression of differentiated trophoblast markers including Tpbp, Gcm1, and Pl-1, and increased expression of the trophoblast stem cell marker Eomes. Alkbh1 localizes to nuclear euchromatin, and interacts strongly with Mrj, an essential placental gene that mediates gene repression by recruitment of class 11 histone deacetylases (HDACs). Competition experiments show Alkbh1 and HDAC4 binding to Mrj are mutually exclusive, which causes decreased HDAC activity and increased target gene expression. Our study demonstrates Alkbh1 performs important functions in placental trophoblast lineage differentiation and participates in mechanisms of transcriptional regulation.