PDF(Pubmed)
Abstract：
Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human diseases remains unexplored. Using isogenic cell lines, patient samples, and a mutant mouse model, we investigated how cancer-associated mutations in SF3B1 alter transcription. We found that these mutations reduce the elongation rate of RNA polymerase II (RNAPII) along gene bodies and its density at promoters. The elongation defect results from disrupted pre-spliceosome assembly due to impaired protein-protein interactions of mutant SF3B1. The decreased promoter-proximal RNAPII density reduces both chromatin accessibility and H3K4me3 marks at promoters. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC/H3K4me pathway, which, when modulated, reverse both transcription and chromatin changes. Our findings reveal how splicing factor mutant states behave functionally as epigenetic disorders through impaired transcription-related changes to the chromatin landscape. We also present a rationale for targeting the Sin3/HDAC complex as a therapeutic strategy.
摘要：
前信使RNA的转录和剪接紧密协调，但是这种功能耦合是如何在人类疾病中被破坏的，还有待探索。使用等基因细胞系，患者样本,和突变小鼠模型，我们调查了SF3B1中癌症相关突变如何改变转录.我们发现这些突变降低了RNA聚合酶II（RNAPII）沿基因体的伸长率及其在启动子处的密度。延伸缺陷是由于突变体SF3B1的蛋白质-蛋白质相互作用受损而导致的剪接体组装前的破坏。降低的启动子近端RNAPII密度降低了染色质可及性和启动子处的H3K4me3标记。通过一个不偏不倚的屏幕，我们确定了Sin3/HDAC/H3K4me途径中的表观遗传因素，which,当调制时，逆转录和染色质变化。我们的发现揭示了剪接因子突变状态如何通过受损的染色质景观转录相关变化在功能上表现为表观遗传疾病。我们还提出了靶向Sin3/HDAC复合物作为治疗策略的基本原理。
