创伤后应激障碍是常见的由创伤性恐惧记忆导致的精神疾病，长期稳定的恐惧消除记忆形成是其治疗成功的关键，其机制尚未完全阐明。申请者前期研究发现抑制表观调控因子ING1表达能阻止恐惧消除记忆形成。既往有研究表明ING1聚集和新型DNA修饰5fC成正相关,而我们近期也发现在恐惧消除中ING1能特异性结合具有5fC修饰的Nr4a2增强子继而激活Nr4a2表达，故推测5fC可能作为上游信号引导ING1调控Nr4a2基因表达而促进恐惧消除记忆形成。本项目拟在恐惧消除小鼠行为学模型中，通过基因组测序技术、分子生物学和表观遗传学完整阐明上述表观调控通路；并利用CRISPR病毒系统介导定点抑制5fC形成或调控Nr4a2表达观察对恐惧消除记忆形成，探讨ING1-5fC-Nr4a2这一新型表观调控通路对恐惧消除记忆形成的影响。本研究将对创伤后应激障碍的治疗机制拓展新的理论视角并为其药物研发提供潜在治疗靶点。

Post-traumatic stress disorder（PTSD）is a common type of mental illness caused by traumatic fear memory, and long-lasting fear extinction memory is the key to its successful treatment； however, the molecular machinery underlies the formation of fear extinction memory is not fully revealed. Inhibitor of growth family member 1 (ING1) is a key epigenetic regulator, which has been proved to be necessary for fear extinction memory. Previous studies have shown that ING1 binding is associated with the accumulation of a recently discovered DNA modification, 5-formylcytosine (5fC). Recently, we have observed that ING1 accumulated at the activated enhancer of the memory-related geneNr4a2 followed by induction of 5fC accumulation and Nr4a2 expression post to fear extinction training. Thus, it is hypothesized that ING1 binds to 5fC and induces Nr4a2 expression is important for the formation of fear extinction memory. This project will adopt genome-wide sequencing technology、molecular and epigenetic tools to fully reveal the proposed epigenetic regulatory machinery. Moreover, in vivo, we will use the viral CRISPR system to perform site-direct manipulation of 5fC accumulation and Nr4a2 expression to examine functional association between ING1, 5fC, and Nr4a2 in extinction memory formation. Successful completion of this project will not only discover a novel neuroepigenetic pathway for extinction but will also provide attractive candidates for the development of new treatments for fear-related disorders.