Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis
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 chr...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56187-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585600245432320 |
|---|---|
| author | Alireza Lorzadeh George Ye Sweta Sharma Unmesh Jadhav |
| author_facet | Alireza Lorzadeh George Ye Sweta Sharma Unmesh Jadhav |
| author_sort | Alireza Lorzadeh |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e0b208edc6ec4a02bb4fdc56157286f6 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e0b208edc6ec4a02bb4fdc56157286f62025-01-26T12:42:06ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-025-56187-0Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasisAlireza Lorzadeh0George Ye1Sweta Sharma2Unmesh Jadhav3Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern CaliforniaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern CaliforniaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern CaliforniaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern CaliforniaAbstract 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.https://doi.org/10.1038/s41467-025-56187-0 |
| spellingShingle | Alireza Lorzadeh George Ye Sweta Sharma Unmesh Jadhav Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis Nature Communications |
| title | Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis |
| title_full | Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis |
| title_fullStr | Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis |
| title_full_unstemmed | Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis |
| title_short | Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis |
| title_sort | motif distribution and dna methylation underlie distinct cdx2 binding during development and homeostasis |
| url | https://doi.org/10.1038/s41467-025-56187-0 |
| work_keys_str_mv | AT alirezalorzadeh motifdistributionanddnamethylationunderliedistinctcdx2bindingduringdevelopmentandhomeostasis AT georgeye motifdistributionanddnamethylationunderliedistinctcdx2bindingduringdevelopmentandhomeostasis AT swetasharma motifdistributionanddnamethylationunderliedistinctcdx2bindingduringdevelopmentandhomeostasis AT unmeshjadhav motifdistributionanddnamethylationunderliedistinctcdx2bindingduringdevelopmentandhomeostasis |