Article PTBP1-activated co-transcriptional splicing controls epigenetic status of pluripotent stem cells
Article PTBP1-activated co-transcriptional splicing controls epigenetic status of pluripotent stem cells
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DOI：
10.1016/j.molcel.2022.12.014
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发表时间：
2023-01-19
期刊：
影响因子：
16
通讯作者：
Makeyev, Eugene V.
中科院分区：
文献类型：
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作者：
Iannone, Camilla;Kainov, Yaroslav;Makeyev, Eugene V.
许多剪接体内含子从RNA聚合酶II （RNA Pol II）产生的新生转录本中切除。细胞类型特异性调控的程度和这种共转录事件的可能功能仍然知之甚少。我们使用急性耗竭方法检测了RNA结合蛋白PTBP1在这一过程中的作用，随后分析了染色质和RNA Pol ii相关转录物。我们发现PTBP1激活了数百个内含子的共转录切除，这是一个令人惊讶的效果，因为已知该蛋白促进内含子保留。重要的是，一些共转录激活的内含子在没有PTBP1的情况下无法完成剪接。在一个显著的例子中，ptbp1依赖性内含子的保留触发了编码DNA甲基转移酶DNMT3B的转录本的无义介导的衰变。我们提供的证据表明，这种调节促进了发育神经元中DNMT3B水平的自然下降，并保护分化特异性基因免受异位甲基化。因此，ptbp1激活的共转录剪接是介导细胞身份表观遗传控制的普遍现象。
Many spliceosomal introns are excised from nascent transcripts emerging from RNA polymerase II (RNA Pol II). The extent of cell-type-specific regulation and possible functions of such co-transcriptional events remain poorly understood. We examined the role of the RNA-binding protein PTBP1 in this process using an acute depletion approach followed by the analysis of chromatin-and RNA Pol II-associated transcripts. We show that PTBP1 activates the co-transcriptional excision of hundreds of introns, a surprising effect given that this protein is known to promote intron retention. Importantly, some co-transcriptionally activated introns fail to complete their splicing without PTBP1. In a striking example, retention of a PTBP1-dependent intron triggers nonsense-mediated decay of transcripts encoding DNA methyltransferase DNMT3B. We provide evidence that this regulation facilitates the natural decline in DNMT3B levels in developing neurons and protects dif-ferentiation-specific genes from ectopic methylation. Thus, PTBP1-activated co-transcriptional splicing is a widespread phenomenon mediating epigenetic control of cellular identity.