Department of Biostatistics and Bioinformatics, Division of Integrative Genomics, Duke University Medical Center, Durham, North Carolina 27708, USA.
Computational Biology and Bioinformatics Graduate Program, Duke University, Durham, North Carolina 27708, USA.
Genome Res. 2021 Apr;31(4):538-550. doi: 10.1101/gr.267898.120. Epub 2021 Mar 5.
The AP-1 transcription factor (TF) dimer contributes to many biological processes and environmental responses. AP-1 can be composed of many interchangeable subunits. Unambiguously determining the binding locations of these subunits in the human genome is challenging because of variable antibody specificity and affinity. Here, we definitively establish the genome-wide binding patterns of five AP-1 subunits by using CRISPR to introduce a common antibody tag on each subunit. We find limited evidence for strong dimerization preferences between subunits at steady state and find that, under a stimulus, dimerization patterns reflect changes in the transcriptome. Further, our analysis suggests that canonical AP-1 motifs indiscriminately recruit all AP-1 subunits to genomic sites, which we term AP-1 hotspots. We find that AP-1 hotspots are predictive of cell type-specific gene expression and of genomic responses to glucocorticoid signaling (more so than super-enhancers) and are significantly enriched in disease-associated genetic variants. Together, these results support a model where promiscuous binding of many AP-1 subunits to the same genomic location play a key role in regulating cell type-specific gene expression and environmental responses.
AP-1 转录因子（TF）二聚体参与许多生物过程和环境反应。AP-1 可以由许多可互换的亚基组成。由于抗体特异性和亲和力的差异，明确确定这些亚基在人类基因组中的结合位置具有挑战性。在这里，我们通过使用 CRISPR 在每个亚基上引入常见的抗体标签，明确确定了五个 AP-1 亚基的全基因组结合模式。我们发现，在稳定状态下，亚基之间的强二聚体偏好的证据有限，并且发现，在刺激下，二聚体模式反映了转录组的变化。此外，我们的分析表明，规范的 AP-1 基序不加区分地将所有 AP-1 亚基募集到基因组位点，我们称之为 AP-1 热点。我们发现，AP-1 热点可预测细胞类型特异性基因表达和糖皮质激素信号转导的基因组反应（比超级增强子更重要），并且在与疾病相关的遗传变异中显著富集。总之，这些结果支持这样一种模型，即许多 AP-1 亚基对同一基因组位置的混杂结合在调节细胞类型特异性基因表达和环境反应中起着关键作用。
