Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
Nat Genet. 2022 Aug;54(8):1238-1247. doi: 10.1038/s41588-022-01132-w. Epub 2022 Jul 21.
Most endogenous retroviruses (ERVs) in mammals are incapable of retrotransposition; therefore, why ERV derepression is associated with lethality during early development has been a mystery. Here, we report that rapid and selective degradation of the heterochromatin adapter protein TRIM28 triggers dissociation of transcriptional condensates from loci encoding super-enhancer (SE)-driven pluripotency genes and their association with transcribed ERV loci in murine embryonic stem cells. Knockdown of ERV RNAs or forced expression of SE-enriched transcription factors rescued condensate localization at SEs in TRIM28-degraded cells. In a biochemical reconstitution system, ERV RNA facilitated partitioning of RNA polymerase II and the Mediator coactivator into phase-separated droplets. In TRIM28 knockout mouse embryos, single-cell RNA-seq analysis revealed specific depletion of pluripotent lineages. We propose that coding and noncoding nascent RNAs, including those produced by retrotransposons, may facilitate 'hijacking' of transcriptional condensates in various developmental and disease contexts.
大多数哺乳动物内源性逆转录病毒（ERVs）不能逆转录转座；因此，ERV 去抑制与早期发育过程中的致死性相关的原因一直是个谜。在这里，我们报告说，异染色质连接蛋白 TRIM28 的快速和选择性降解触发了转录凝聚体从编码超级增强子（SE）驱动的多能性基因的位置上解离，并与小鼠胚胎干细胞中转录的 ERV 位置发生关联。ERV RNA 的敲低或 SE 富集转录因子的强制表达挽救了 TRIM28 降解细胞中凝聚体在 SE 处的定位。在生化重构系统中，ERV RNA 促进了 RNA 聚合酶 II 和共激活因子 Mediator 进入相分离液滴。在 TRIM28 敲除小鼠胚胎中，单细胞 RNA-seq 分析显示多能性谱系特异性耗竭。我们提出，包括逆转座子产生的编码和非编码新生 RNA 在内，可能会在各种发育和疾病情况下促进转录凝聚体的“劫持”。
