HP1c通过负调控Notch信号通路维持肠道稳态的表观遗传机制

The function of gut is maintained by gut stem cells, which can self-renew and differentiate to protect the tissue form functional degradation, damage and inflammation. As the construction of Drosophila midgut is similar to that of mammals, investigating the mechanisms of gut stem cell self-renewal and differentiation is critical for understanding the gut diseases and finding the drug target. In recent years, chromatin regulation of gene expression has been identified as a major intrinsic epigenetic mechanism for stem cell fate determination. However, the epigenetic regulation of gut stem cell homeostasis has more to be understood. In our previous study, we found that the chromatin binding protein HP1c plays a key role in regulating homeostasis and cell fate in Drosophila intestine, whose downregulation resulted in decrease of intestinal stem cell number and differentiation defect. Meanwhile, HP1c also functions to suppress gastrointestinal tumors. Further studies found that the regulatory role of HP1c for intestinal homeostasis is mainly achieved through the negative regulation of Notch signaling pathway. In our future researches, we will further confirm the regulatory role of HP1c on Notch signaling pathway, uncover its molecular mechanism, and explore the biological meanings under both physiological and pathological conditions. This project will help us improve our understanding of the mechanism of intestinal homeostasis and provide a new sight for the treatment of gut diseases.

肠道的功能维持依赖肠道干细胞的自我更新与分化的平衡，以抵抗老化、损伤及炎症等不利条件。成体果蝇肠道结构与哺乳动物相似，研究其肠道干细胞增殖与分化的调控机理对于认识和治疗肠道疾病具有重要意义。近年来以染色质为核心的表观遗传调控被视为决定干细胞命运的关键因素，然而果蝇肠道稳态的表观遗传调控机制仍待深入研究。在本项目中，我们发现HP1c作为表观遗传调控因子，在果蝇肠道干细胞的稳态维持和分化过程中发挥重要作用，其缺失引起肠道干细胞减少和分化紊乱。此外，HP1c对于消化道肿瘤的产生具有抑制作用。进一步研究发现，HP1c在消化道稳态调控中的作用主要是通过负调控Notch信号通路实现的。本项目将进一步确认HP1c对Notch信号通路的调控作用及其分子机制，并探究该调控作用在生理和病理状态下对果蝇消化道系统的生物学影响。这将有助于我们提高对于肠道疾病发生机制的认识，为临床治疗以及药物开发提供新的理论依据。

已知大多数多细胞生物中，Notch信号和表观遗传因子在调节组织稳态中发挥关键作用，但Notch信号如何与表观遗传因子协调以控制分化仍不清楚。在这里，我们确定异染色质蛋白1c（HP1c）是果蝇肠道稳态的重要表观遗传调节因子。具体而言，我们观察到HP1c功能丧失表型类似于Notch信号干扰后观察到的表型，并且HP1c在遗传上与Notch通路的成分相互作用。HP1c通过与Notch信号传导的关键转录因子Su（H）直接相互作用来抑制Notch靶基因的转录。此外，通过表达人类HP1c（HP1γ）可以挽救果蝇中HP1c缺失引起的表型，这表明HP1c的功能具有保守性。总之，我们的发现揭示了HP1c通过抑制Notch信号在正常发育和肠道稳态中的重要作用。