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.

前信使 RNA 的转录和剪接是密切协调的，但这种功能耦合在人类疾病中如何被破坏仍有待探索。使用同基因细胞系、患者样本和突变小鼠模型，我们研究了 SF3B1 中与癌症相关的突变如何改变转录。我们发现这些突变降低了 RNA 聚合酶 II (RNAPII) 沿基因体的延伸率及其在启动子处的密度。伸长缺陷是由于突变体 SF3B1 的蛋白质-蛋白质相互作用受损而导致剪接体前组装破坏造成的。启动子近端 RNAPII 密度的降低降低了启动子处的染色质可及性和 H3K4me3 标记。通过公正的筛选，我们确定了 Sin3/HDAC/H3K4me 通路中的表观遗传因子，这些因子在受到调节时会逆转转录和染色质的变化。我们的研究结果揭示了剪接因子突变状态如何通过受损的转录相关染色质景观变化而表现出表观遗传疾病的功能。我们还提出了将 Sin3/HDAC 复合物作为治疗策略的基本原理。