Chronic inflammation is a well-established risk factor for cancer, but the underlying molecular mechanisms remain unclear1,2. Using a mouse model of colitis, we demonstrate that colonic stem cells retain an epigenetic memory of inflammation following disease resolution that persists for more than 100 days. Here we find that memory of colitis is characterized by a cumulative gain of activator protein 1 (AP-1) transcription factor activity, with durable changes to chromatin accessibility. Further, we develop SHARE-TRACE, a method that enables simultaneous profiling of gene expression, chromatin accessibility and clonal history in single cells, enabling high-resolution tracking of epigenomic memory. This approach reveals that memory of colitis is propagated cell-intrinsically and inherited through stem cell divisions, with some clones demonstrating stronger memory than others. Finally, we show that colitis primes stem cells for increased expression of an AP-1-regulated gene program following oncogenic mutation that accelerates tumour growth, a phenotype dependent on AP-1 activity. Together, our findings provide a mechanistic link between chronic inflammation and malignancy, revealing how long-lived epigenetic alterations in regenerative tissues may contribute to disease susceptibility and suggesting potential diagnostic and therapeutic strategies to mitigate cancer risk in patients with chronic inflammatory conditions.
慢性炎症是癌症的一个明确风险因素，但其潜在的分子机制尚不清楚1,2。通过使用结肠炎小鼠模型，我们证明结肠干细胞在炎症消退后仍保留着表观遗传记忆，这种记忆可持续超过100天。本研究发现，结肠炎记忆的特征在于激活蛋白1（AP-1）转录因子活性的累积增强，以及染色质可及性的持久改变。此外，我们开发了SHARE-TRACE方法，该方法能够在单细胞中同时分析基因表达、染色质可及性和克隆历史，从而实现对表观遗传记忆的高分辨率追踪。该方法揭示，结肠炎记忆以细胞内在方式传播，并通过干细胞分裂遗传，其中某些克隆表现出比其他克隆更强的记忆。最后，我们发现，结肠炎会使干细胞在发生致癌突变后更易上调AP-1调控的基因程序，从而加速肿瘤生长，这一表型依赖于AP-1活性。综上所述，我们的研究结果揭示了慢性炎症与恶性肿瘤之间的机制联系，阐明了再生组织中持久的表观遗传改变如何影响疾病易感性，并为降低慢性炎症性疾病患者癌症风险提供了潜在的诊断和治疗策略。
肿瘤(癌症)患者之家