The Trans-Activator RNF12 and Cis-Acting Elements Effectuate X Chromosome Inactivation Independent of X-Pairing
The Trans-Activator RNF12 and Cis-Acting Elements Effectuate X Chromosome Inactivation Independent of X-Pairing
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DOI：
10.1016/j.molcel.2014.02.006
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发表时间：
2014-03-20
期刊：
影响因子：
16
通讯作者：
Gribnau, Joost
中科院分区：
文献类型：
--
作者：
Barakat, Tahsin Stefan;Loos, Friedemann;Gribnau, Joost
雌性胎盘哺乳动物的X染色体失活（XCI）是X连锁基因和常染色体基因之间剂量补偿的重要机制。XCI始于Xist的激活和负调控因子Tsix的沉默，随后Xist RNA在未来的失活X染色体（Xi）上顺式扩散。在此，我们表明XCI不需要两条X染色体之间的物理接触（X配对），而是由反式作用的可扩散因子调控。我们发现X编码的反式作用且剂量依赖的XCI激活因子RNF12与包含Jpx、Ftx和Xpr的顺式调控区域协同作用，以激活Xist并克服Tsix的抑制。RNF12在两个后续步骤中起作用；两个有活性的Rnf12拷贝驱动XCI的起始，并且一个拷贝需要保持活性以在Xi建立过程中维持XCI。这种两步机制确保XCI非常稳健且精细调节，防止两条X染色体都发生XCI。
X chromosome inactivation (XCI) in female placental mammals is a vital mechanism for dosage compensation between X-linked and autosomal genes. XCI starts with activation of Xist and silencing of the negative regulator Tsix, followed by cis spreading of Xist RNA over the future inactive X chromosome (Xi). Here, we show that XCI does not require physical contact between the two X chromosomes (X-pairing) but is regulated by trans-acting diffusible factors. We found that the X-encoded trans-acting and dose-dependent XCI-activator RNF12 acts in concert with the cis-regulatory region containing Jpx, Ftx, and Xpr to activate Xist and to overcome repression by Tsix. RNF12 acts at two subsequent steps; two active copies of Rnf12 drive initiation of XCI, and one copy needs to remain active to maintain XCI toward establishment of the Xi. This two-step mechanism ensures that XCI is very robust and fine-tuned, preventing XCI of both X chromosomes.