Cooperation of chromatin remodeling SWI/SNF complex and pioneer factor AP1 shapes 3D enhancer landscapes [SWI_SNF_complex]

The mechanism controlling the dynamic targeting of SWI/SNF has long been postulated to be coordinated by transcription factors (TFs), yet identifying and demonstrating the influence of different TFs has proven difficult. In this study we take a multi-omics approach to directly interrogate transient SWI/SNF interactors, chromatin targeting, and the plasticity of the resulting 3D epigenetic landscape. We utilized the novel proximity based labeling technique TurboID to identify the AP1 family as a critical interacting partner for endogenous SWI/SNF complexes. Validation through CUT&RUN profiling demonstrated SWI/SNF targeting enrichment at AP1 bound loci, and SWI/SNF – AP1 cooperation in chromatin targeting. Mapping of 3D chromatin structure via HiChIP revealed AP1-SWI/SNF dependent restructuring of promoter-enhancer architecture and generation of enhancer hubs, ultimately regulating transcription. Through direct interrogation of the SWI/SNF – AP1 interaction, we demonstrate a SWI/SNF functional dependency on AP1 mediated chromatin localization. We propose that pioneer factors such as AP1 bind and target SWI/SNF to inactive chromatin, where it restructures the genomic landscape into an active state through epigenetic rewiring spanning multiple dimensions. Time course CUT&RUN profiling of ARID1A, PBRM1 and BRD9 in inducible SMARCB1 G401 cell line

长期以来，学界推测SWI/SNF复合物动态靶向的调控机制由转录因子（Transcription Factors，TFs）协同介导，但鉴定并验证不同转录因子的调控作用始终颇具难度。本研究采用多组学策略，直接探究SWI/SNF复合物的瞬时互作蛋白、染色质靶向特性及其所介导的三维表观遗传景观可塑性。本研究借助新型邻近标记技术TurboID，鉴定出AP1家族是内源性SWI/SNF复合物的关键互作伴侣。通过CUT&RUN测序图谱分析进行验证，结果显示SWI/SNF复合物在AP1结合位点处存在靶向富集，且SWI/SNF与AP1在染色质靶向过程中存在协同作用。借助HiChIP技术绘制三维染色质结构图谱，结果证实AP1-SWI/SNF依赖型的启动子-增强子架构重塑以及增强子枢纽的形成，最终实现转录调控。通过直接探究SWI/SNF与AP1的互作关系，本研究证实SWI/SNF复合物的功能依赖于AP1介导的染色质定位。本研究提出，AP1等先驱因子可结合并将SWI/SNF复合物靶向募集至非活性染色质区域，随后SWI/SNF通过多维度表观遗传重编程，将基因组景观重塑为活性状态。对诱导型SMARCB1 G401细胞系中的ARID1A、PBRM1及BRD9进行时序CUT&RUN图谱分析