Gene transcription is coordinately regulated by multiple transcription factors. However, a systematic approach is still lacking to identify co-regulators for transcription factors. Here, we performed ChIP-Seq analysis and predicted the regulators for p53-mediated transcription process, from which we confirmed the roles of GLIS2, MAZ and MEF2A in regulating p53 target genes. We revealed that GLIS2 selectively regulates the transcription of PUMA but not p21. GLIS2 deficiency caused the elevation of H3K27ac and p53 binding on the PUMA enhancer, and promoted PUMA expression. It increased the rate of apoptosis, but not cell cycle. Moreover, GLIS2 represses H3K27ac level on enhancers, regulates the gene expression related with focal adhesion and promotes cell migration, through inhibiting p300. Big data analysis supports GLIS2 as an oncogene in colon cancer, and perhaps other cancers. Taken together, we have predicted candidates for p53 transcriptional regulators, and provided evidence for GLIS2 as an oncogene through repressing enhancer activation.

基因转录受多种转录因子的协调调控。然而，仍然缺乏系统的方法来鉴定转录因子的共调节子。在这里，我们进行了ChIP-Seq分析并预测了p53介导的转录过程的调控因子，从中我们证实了GLIS2，MAZ和MEF2A在调控p53靶基因中的作用。我们发现GLIS2选择性调节PUMA的转录而不是p21的转录。GLIS2缺乏引起PUMA增强子上H3K27ac和p53结合的升高，并促进了PUMA表达。它增加了细胞凋亡的速率，但没有增加细胞周期。此外，GLIS2通过抑制p300来抑制增强子上的H3K27ac水平，调节与粘着斑有关的基因表达并促进细胞迁移。大数据分析支持GLIS2作为结肠癌甚至其他癌症的癌基因。综上所述，我们已经预测了p53转录调节子的候选物，并通过抑制增强子的激活为GLIS2作为致癌基因提供了证据。