Nuclear Argonaute proteins, guided to nascent target RNAs by their bound small RNAs, elicit co-transcriptional silencing through heterochromatin formation at transposon insertions and repetitive genomic loci. The molecular mechanisms involved in this process are incompletely understood. Here, we propose that the SFiNX complex, a silencing mediator downstream of nuclear Piwi-piRNA complexes in Drosophila, enables co-transcriptional silencing via the formation of molecular condensates. Condensate formation is stimulated by nucleic acid binding and requires SFiNX dimerization, mediated by the dynein light chain protein, LC8/Cutup. LC8’s function within SFiNX can be bypassed with a heterologous dimerization domain, suggesting that dimerization is a constitutive feature of SFiNX. Mutations preventing LC8-mediated SFiNX dimerization result in loss of condensate formation in vitro and inability of Piwi to initiate heterochromatin formation and silence transposons in vivo. Formation of molecular condensates might be a general mechanism that underlies effective heterochromatin establishment at small RNA target loci in a co-transcriptional manner.

中文翻译：

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通过二聚体SFiNX复合体进行的Piwi介导的共转录沉默的分子原理

核Argonaute蛋白通过其结合的小RNA引导至新生的目标RNA，通过在转座子插入处的异染色质形成和重复的基因组位点引起共转录沉默。此过程涉及的分子机制尚未完全了解。在这里，我们提出SFiNX复合物，果蝇核Piwi-piRNA复合物下游的沉默介体。通过分子缩合物的形成实现共转录沉默。凝结物的形成受核酸结合的刺激，需要SFiNX二聚化，由达因轻链蛋白LC8 / Cutup介导。SFiNX中LC8的功能可以通过异源二聚化域来绕开，这表明二聚化是SFiNX的构成特征。阻止LC8介导的SFiNX二聚化的突变会导致体外凝结水的损失，以及Piwi无法在体内引发异染色质的形成和沉默转座子。分子缩合物的形成可能是以共转录方式在小RNA靶基因座上有效建立异染色质的基础的一般机制。