Lorzadeh Alireza, Ye George, Sharma Sweta, Jadhav Unmesh
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Nat Commun. 2025 Jan 22;16(1):929. doi: 10.1038/s41467-025-56187-0.
Transcription factors guide tissue development by binding to developmental stage-specific targets and establishing an appropriate enhancer landscape. In turn, DNA and chromatin modifications direct the genomic binding of transcription factors. However, how transcription factors navigate chromatin features to selectively bind a small subset of all the possible genomic target loci remains poorly understood. Here we show that Cdx2-a lineage defining transcription factor that binds distinct targets in developing versus adult intestinal epithelial cells-has a preferential affinity for a non-canonical CpG-containing motif in vivo. A higher frequency of this motif at embryonic Cdx2 targets and methylated state of the CpG during development enables selective Cdx2 binding and activation of developmental enhancers and genes. In adult cells, demethylation at these enhancers prevents ectopic Cdx2 binding, instead directing Cdx2 to its canonical motif without a CpG. This shift in Cdx2 binding facilitates Ctcf and Hnf4 recruitment, establishing super-enhancers during development and homeostatic enhancers in adult cells, respectively. Induced DNA methylation in adult mouse epithelium or cultured cells recruits Cdx2 to developmental targets, promoting corecruitment of partner transcription factors. Thus, Cdx2's differential CpG motif preferences enable it to navigate distinct DNA methylation profiles, activating genes specific to appropriate developmental stages.
转录因子通过结合发育阶段特异性靶标并建立合适的增强子景观来指导组织发育。反过来，DNA和染色质修饰指导转录因子的基因组结合。然而，转录因子如何在染色质特征中导航以选择性地结合所有可能的基因组靶位点中的一小部分，目前仍知之甚少。在这里，我们表明Cdx2——一种在发育中的与成年肠上皮细胞中结合不同靶标的谱系定义转录因子——在体内对一种非规范的含CpG基序具有优先亲和力。在胚胎Cdx2靶标处这种基序的较高频率以及发育过程中CpG的甲基化状态使得Cdx2能够选择性结合并激活发育增强子和基因。在成年细胞中，这些增强子处的去甲基化可防止异位Cdx2结合，而是将Cdx2导向其不含CpG的规范基序。Cdx2结合的这种转变分别促进了Ctcf和Hnf4的募集，在发育过程中建立超级增强子，在成年细胞中建立稳态增强子。在成年小鼠上皮或培养细胞中诱导DNA甲基化会将Cdx2募集到发育靶标，促进伙伴转录因子的共募集。因此，Cdx2不同的CpG基序偏好使其能够在不同的DNA甲基化图谱中导航，激活特定于适当发育阶段的基因。
