Xu Siyuan, Peng Chuxuan, Ren Ren, Lu Haowen, Zhao Han, Xia Sijian, Shen Yijie, Xu Bin, Zhang Haoyue, Cheng Xiaodong, Blobel Gerd A, Lan Xianjiang
Department of Systems Biology for Medicine, School of Basic Medical Sciences, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Rep. 2025 Apr 22;44(4):115476. doi: 10.1016/j.celrep.2025.115476. Epub 2025 Mar 28.
The clustering of multiple transcription factor binding sites (TFBSs) for the same TF has proved to be a pervasive feature of cis-regulatory elements in the eukaryotic genome. However, the contribution of binding sites within the homotypic clusters of TFBSs (HCTs) to TF binding and target gene expression remains to be understood. Here, we characterize the CHD4 enhancers that harbor unique functional ZNF410 HCTs genome wide. We uncover that ZNF410 controls chromatin accessibility and activity of the CHD4 enhancer regions. We demonstrate that ZNF410 binds to the HCTs in a collaborative fashion, further conferring transcriptional activation. In particular, three ZNF410 motifs (sub-HCTs) located at 3' end of the distal enhancer act as "switch motifs" to control chromatin accessibility and enhancer activity. Mechanistically, the SWI/SNF complex is selectively required to mediate cooperative ZNF410 binding for CHD4 expression. Together, our findings expose a complex functional hierarchy of homotypic clustered motifs, which cooperate to fine-tune target gene expression.
同一转录因子的多个转录因子结合位点（TFBS）聚集已被证明是真核基因组顺式调控元件的一个普遍特征。然而，TFBS同型簇（HCT）内的结合位点对转录因子结合和靶基因表达的贡献仍有待了解。在这里，我们在全基因组范围内对含有独特功能性ZNF410 HCT的CHD4增强子进行了表征。我们发现ZNF410控制CHD4增强子区域的染色质可及性和活性。我们证明ZNF410以协同方式与HCT结合，进一步赋予转录激活作用。特别是，位于远端增强子3'端的三个ZNF410基序（亚HCT）作为“开关基序”来控制染色质可及性和增强子活性。从机制上讲，SWI/SNF复合物是介导ZNF410协同结合以实现CHD4表达所必需的。总之，我们的研究结果揭示了同型簇状基序的复杂功能层次结构，它们协同作用以微调靶基因表达。
