神经内分泌（NE）小细胞肺癌（SCLC）的获得性耐药与DNA损伤修复通路的异常有关。我们发现MEN1基因敲除（MEN1Δ/Δ）引起DNA双链断裂（DSB）的累积和基因组不稳定，促进NE肺癌的发生发展，其编码蛋白menin促进同源重组修复而抑制非同源末端连接修复因子招募至DSB位点；menin/MLL复合物及其催化的染色质H3K4me3在DSB位点富集，该复合物缺失减小细胞核体积，增加DSB的形成速率。我们推测menin/MLL在DSB位点催化H3K4me3修饰，增加染色质可接近性从而调控修复因子的招募和DSB的修复。本项目拟利用MEN1Δ/Δ、MLLΔ/Δ及NE肺癌小鼠模型进一步证实menin/MLL在DSB修复中的作用。采用ChIP、ATAC-seq、3C等技术探讨menin/MLL调控DSB修复的染色质重塑机制，从表观遗传学角度解析SCLC获得性耐药机制，为开发靶向治疗药物提供新思路。

Acquired resistance of neuroendocrine (NE) small cell lung cancer (SCLC) is associated with abnormal DNA damage repair pathways. We found that the knockout of MEN1 gene (MEN1Δ/Δ) caused DNA double-strand break (DSB) accumulation, increased genomic instability, and promoted the development and progression of NE lung cancer. menin protein, encoded by MEN1, promotes homologous recombination repair factors while inhibits non-homologous end joining repair factors recruit to DSB sites. menin/MLL complex and its catalyzed chromatin H3K4me3 were enriched at DSB sites, and deficiency of menin/MLL complex diminishes the nuclear volumes and enhances the formation rates of DSB. We speculate that menin/MLL catalyzes H3K4me3 modification at the DSB sites, increases chromatin accessibility to regulate the recruitment of repair factors and the repair of DSB. In this study, the MEN1Δ/Δ, MLLΔ/Δ and NE lung cancer mouse models were used to confirm the roles of menin/MLL in DSB repair. To explore the mechanism of chromatin remodeling for menin/MLL regulates DSB repair by using ChIP, ATAC-seq, and 3C technologies. The project will analyze the mechanisms of SCLC acquired resistance from the perspective of epigenetics, and provide a novel idea for the development of SCLC therapeutic drugs.