Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis.
Publication Year:
2025
PubMed ID:
39843425
Funding Grants:
Public Summary:
Developing and adult intestinal cells need different sets of genes to build the intestine and keep it functioning. Researchers investigated how a protein called CDX2 helps switch on the right genes at each stage. They found that CDX2 recognizes specific DNA sequences and responds to chemical tags on DNA, called methylation marks. During development, these tags help guide CDX2 to genes involved in building intestinal tissue. In adult cells, removal of the tags redirects CDX2 toward genes that maintain normal intestinal function. Adding the tags back to adult cells drew CDX2 to developmental targets again and helped recruit other gene-controlling proteins. These findings explain how DNA sequences and chemical tags work together to guide the same protein toward different tasks as tissues develop and mature.
Scientific Abstract:
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.