DNA methylation-dependent and -independent binding of CDX2 directs activation of distinct developmental and homeostatic genes
Bibliographic record
Abstract
Abstract Precise spatiotemporal and cell type-specific gene expression is essential for proper tissue development and function. Transcription factors (TFs) guide this process by binding to developmental stage-specific targets and establishing an appropriate enhancer landscape. In turn, DNA and chromatin modifications direct the genomic binding of TFs. However, how TFs navigate various chromatin features and selectively bind a small portion of the millions of possible genomic target loci is still not well understood. Here we show that Cdx2 - a pioneer TF 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 and fetal Cdx2 target loci and the specifically methylated state of the CpG during development allows selective Cdx2 binding and activation of developmental enhancers and linked genes. Conversely, demethylation at these enhancers prohibits ectopic Cdx2 binding in adult cells, where Cdx2 binds its canonical motif without a CpG. This differential Cdx2 binding allows for corecruitment of Ctcf and Hnf4, facilitating the establishment of intestinal superenhancers during development and enhancers mediating adult homeostatic functions, respectively. Induced gain of DNA methylation in the adult mouse epithelium or cultured cells causes ectopic recruitment of Cdx2 to the developmental target loci and facilitates cobinding of the partner TFs. Together, our results demonstrate that the differential CpG motif requirements for Cdx2 binding to developmental versus adult target sites allow it to navigate different DNA methylation profiles and activate cell type-specific genes at appropriate times. Graphical Abstract
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".