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by claude@2026-07, 2026-07-04
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This study investigated how CTCF, a key DNA-binding protein involved in 3D genome organization, controls embryonic development by using gastruloids and a degron system to deplete CTCF at specific timepoints. The authors found that depleting CTCF early disrupted early gastruloid morphogenesis, while differentiation was unaffected as assessed by ATAC-seq and time-resolved RNA-seq. CTCF binding was enriched at promoters of downregulated genes, and re-expression of an N-terminal truncation variant that cannot support looping rescued promoter-bound gene expression and the early morphogenesis defects. However, when gastruloids with the looping-incompetent CTCF variant were cultured longer (up to 168 hours), they collapsed, indicating a later-stage requirement for CTCF’s looping function; The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Summary CTCF is an essential DNA binding protein whose absence leads to embryonic lethality. CTCF is primarily known for its role in 3D genome organization where its N-terminal domain interacts with cohesin to anchor chromatin loops. How CTCF facilitates proper embryonic development remains unclear, necessitating temporal control to resolve its stage-specific functions. By combining gastruloids, an in vitro model of embryonic development, with a degron system to rapidly deplete CTCF at defined timepoints, we show that early CTCF depletion impairs early gastruloid morphogenesis. Surprisingly, ATAC-seq and time-resolved RNA-seq revealed that differentiation was unaffected. CTCF binding is strongly enriched at promoters of downregulated genes. Re-expression of a CTCF variant with an N-terminal truncation, incapable of looping, was sufficient to rescue the expression of CTCF-promoter bound genes and the defects in morphogenesis. However, extended culture (up to 168 hours) of gastruloids reconstituted with N-terminal truncated CTCF led to their collapse. Our work shows that CTCF has a dual function in early mammalian development: at early stages CTCF regulates developmentally important genes through promoter binding, while at later stages its looping function is required for correct development. Highlights CTCF is essential for gastruloid morphogenesis but dispensable for cell differentiation CTCF activates genes through promoter binding CTCF promoter target regulation drives in vitro gastrulation Post-gastrulation development in vitro is driven by CTCF’s looping function
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Summary
CTCF is an essential DNA binding protein whose absence leads to embryonic lethality. CTCF is primarily known for its role in 3D genome organization where its N-terminal domain interacts with cohesin to anchor chromatin loops. How CTCF facilitates proper embryonic development remains unclear, necessitating temporal control to resolve its stage-specific functions. By combining gastruloids, an in vitro model of embryonic development, with a degron system to rapidly deplete CTCF at defined timepoints, we show that early CTCF depletion impairs early gastruloid morphogenesis. Surprisingly, ATAC-seq and time-resolved RNA-seq revealed that differentiation was unaffected. CTCF binding is strongly enriched at promoters of downregulated genes. Re-expression of a CTCF variant with an N-terminal truncation, incapable of looping, was sufficient to rescue the expression of CTCF-promoter bound genes and the defects in morphogenesis. However, extended culture (up to 168 hours) of gastruloids reconstituted with N-terminal truncated CTCF led to their collapse. Our work shows that CTCF has a dual function in early mammalian development: at early stages CTCF regulates developmentally important genes through promoter binding, while at later stages its looping function is required for correct development.
Highlights
CTCF is essential for gastruloid morphogenesis but dispensable for cell differentiation
CTCF activates genes through promoter binding
CTCF promoter target regulation drives in vitro gastrulation
Post-gastrulation development in vitro is driven by CTCF’s looping function
Competing Interest Statement
The authors have declared no competing interest.
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