BRM/BRG1是关键染色体重构复合物SWI/SNF的催化活性亚基，通常BRG1高表达于非成熟肝细胞而BRM正好相反，二者呈“接力”表达现象，协调控制着肝脏分化和各种功能。但我们发现BRG1单独缺失对肝脏发育及再生并无影响，尽管两者都经历了剧烈的染色质重构过程。然而，在人和小鼠肝癌（HCC）组织中，BRM显著下降而BRG1明显上升，提示二者表达时象紊乱与HCC发生密切相关，其功能并不能完全互补。有趣的是BRG1敲除小鼠在DEN诱导下更易成瘤并早发肺转移。SWI/SNF通过染色质构象参与众多基因的转录调控，但BRM/BRG1亚基调控的靶基因并不清楚。本研究将通过BRM/BRG1单独和联合敲除小鼠，建立化学诱导及Mdr2-/-自发HCC小鼠模型，探究BRM/BRG1在肝细胞增殖、分化、EMT及恶性转化中的作用及分子机制，为阐明HCC发生机制及合理干预提供实验基础。

Both BRM and BRG1 are the catalytic subunits of the SWI/SNF complex, which acts crucial role in chromatin remodeling and transcriptional regulation. BRG1 often highly expresses in non-mature hepatocytes including fetal liver and hepatic progenitors in the mature liver, on the contrary, BRM always highly expresses in mature hepatocytes. The relay expressing manner of BRM and BRG1 coordinately controls liver differentiation and function. We have found that the liver selective deletion of BRG1 alone does not disturb the development and regeneration of the liver, although both of them had undergone a progress of intensive chromatin remodeling. However, in human and mouse liver cancer (HCC) tissues, BRM was found significantly decreased while BRG1 was significantly increased, suggesting that the disorder expression of BRM/BRG1 is closely related to the occurrence of HCC. Intriguingly, when induced by DEN injection, BRG1 deficient mice were more likely to be tumorigenic and showed early lung metastases. SWI/SNF is involved in the transcriptional regulation of many genes by controlling chromatin remodeling, but the target genes regulated by BRM/BRG1 subunits remain unclear. In this study, we will generate BRM or/and BRG1 knockout mice and treat the mice with carcinogenic chemicals or induce spontaneous HCC tumors by cross-breeding with Mdr2-/- mice, and then explore the roles of BRM/BRG1 in hepatic proliferation, differentiation, epithelial-mesenchymal transition as well as malignant transformation of hepatocytes. Our work will be helpful to provide experimental foundation for elucidating the mechanism of HCC and reasonable intervention.