ADNP modulates SINE B2-derived CTCF-binding sites during blastocyst formation in mice

CTCF is crucial for chromatin structure and transcription regulation in early embryonic development.However, the

kinetics of CTCF chromatin occupation in preimplantation embryos have remained unclear. In this study, we used

CUT&RUN technology to investigate CTCF occupancy in mouse preimplantation development. Our findings revealed

that CTCF begins binding to the genome prior to zygotic genome activation (ZGA), with a preference for

CTCF-anchored chromatin loops. Although the majority of CTCF occupancy is consistently maintained, we

identified a specific set of binding sites enriched in the mouse-specific short interspersed element (SINE) family B2

that are restricted to the cleavage stages. Notably,we discovered that the neuroprotective protein ADNPcounteracts

the stable association of CTCF at SINE B2-derived CTCF-binding sites. Knockout of Adnp in the zygote led to

impaired CTCF binding signal recovery, failed deposition of H3K9me3, and transcriptional derepression of SINE B2

during the morula-to-blastocyst transition, which further led to unfaithful cell differentiation in embryos around

implantation. Our analysis highlights an ADNP-dependent restriction of CTCF binding during cell differentiation in

preimplantation embryos. Furthermore, our findings shed light on the functional importance of transposable elements

(TEs) in promoting genetic innovation and actively shaping the early embryo developmental process specific

to mammals.