PDF(Pubmed)
Abstract：
Inflammation is essential to the disruption of tissue homeostasis and can destabilize the identity of lineage-committed epithelial cells. Here, we employ lineage-traced mouse models, single-cell transcriptomic and chromatin analyses, and CUT&TAG to identify an epigenetic memory of inflammatory injury in the pancreatic acinar cell compartment. Despite resolution of pancreatitis, our data show that acinar cells fail to return to their molecular baseline, with retention of elevated chromatin accessibility and H3K4me1 at metaplasia genes, such that memory represents an incomplete cell fate decision. In vivo, we find this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second insult but increased tumorigenesis with an oncogenic Kras mutation. The lowered threshold for oncogenic transformation, in turn, can be restored by blockade of MAPK signaling. Together, we define the chromatin dynamics, molecular encoding, and recall of a prolonged epigenetic memory of inflammatory injury that impacts future responses but remains reversible.
摘要：
炎症对于组织稳态的破坏是必不可少的，并且可以破坏谱系定型上皮细胞的身份。这里,我们使用谱系追踪小鼠模型，单细胞转录组学和染色质分析，和CUT&TAG来鉴定胰腺腺泡细胞区室炎症损伤的表观遗传记忆。尽管胰腺炎消退，我们的数据显示腺泡细胞无法恢复到它们的分子基线，随着染色质可及性升高和H3K4me1保留在化生基因，这样记忆代表了一个不完整的细胞命运决定。在体内,我们发现这种表观遗传记忆控制着谱系可塑性，对第二次损伤的反应，化生减少，但伴随致癌Kras突变的肿瘤发生增加。降低了致癌转化的阈值，反过来,可以通过阻断MAPK信号来恢复。一起,我们定义染色质动力学，分子编码，和回忆炎症损伤的长期表观遗传记忆，影响未来的反应，但仍然是可逆的。
