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
Chuxuan Peng
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
Ren Ren
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Haowen Lu
Department of Urology, School of Medicine, Affiliated Zhongda Hospital of Southeast University, Nanjing 210009, China
Han Zhao
Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen 518132, China
Sijian Xia
Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen 518132, China; Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China
Yijie Shen
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
Bin Xu
Department of Urology, School of Medicine, Affiliated Zhongda Hospital of Southeast University, Nanjing 210009, China
Haoyue Zhang
Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen 518132, China
Xiaodong Cheng
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Gerd A. Blobel
Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Xianjiang Lan
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; Corresponding author
Summary: 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.
