Clonal memory of colitis accumulates and promotes tumor growth [IVFP]

Chronic inflammation is a well-established risk factor for cancer, but the underlying molecular mechanisms remain unclear. Using a mouse model of colitis, we demonstrate that colonic stem cells retain an epigenetic memory of inflammation following disease resolution that persists for over 100 days. We find memory of colitis to be characterized by a cumulative gain of activator protein 1 (AP-1) transcription factor activity, with more durable changes to chromatin as well. 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 reveals that inflammatory memory is propagated cell-intrinsically and inherited through stem cell lineages, with certain clones demonstrating dramatically stronger memory than others. Finally, we show that colitis primes stem cells for amplified expression of regenerative gene programs following oncogenic mutation that accelerates tumor growth and this phenotype is 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 therapeutic strategies to mitigate cancer risk in patients with chronic inflammatory conditions. Overall design: To examine binding relationships between AP-1 factors and FOX transcrption factors, in vitro binding assays were performed. Purified transcription factor proteins were incubated with cloned naked DNA sequences and binding was assessed using Tn5 transposition.

慢性炎症是公认的癌症风险因子，但其潜在分子机制仍未阐明。本研究利用结肠炎小鼠模型，证实结直肠干细胞在疾病缓解后仍可留存炎症相关的表观遗传记忆，该记忆可持续超过100天。研究发现，结肠炎相关记忆的特征为激活蛋白1（AP-1）转录因子活性的累积上调，同时伴随染色质结构的持久性改变。此外，我们开发了SHARE-TRACE技术，该方法可同时对单细胞内的基因表达、染色质可及性与克隆历史进行联合分析，从而实现表观遗传记忆的高分辨率追踪。该分析揭示，炎症记忆以细胞自主的方式传递，并通过干细胞谱系进行遗传，部分克隆展现出显著更强的记忆特性。最后，本研究证实，结肠炎可使干细胞在发生致癌突变后，其再生相关基因程序的表达出现增强扩增，进而加速肿瘤生长，且该表型依赖于AP-1的转录活性。综上，本研究揭示了慢性炎症与恶性肿瘤之间的潜在机制关联，阐明了再生组织中长期存在的表观遗传改变如何影响疾病易感性，并为慢性炎症性疾病患者的癌症风险防控提供了潜在治疗策略。整体实验设计：为探究AP-1转录因子与FOX转录因子之间的结合调控关系，本研究开展了体外结合实验。将纯化后的转录因子蛋白与克隆得到的裸露DNA序列共孵育，通过Tn5转座反应评估蛋白与DNA的结合情况。