Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Genes Dev. 2024 Mar 22;38(3-4):168-188. doi: 10.1101/gad.351189.123.
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 ADNP counteracts the stable association of CTCF at SINE B2-derived CTCF-binding sites. Knockout of 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.
CTCF 对于胚胎早期发育中的染色质结构和转录调控至关重要。然而，在着床前胚胎中，CTCF 染色质占据的动力学仍然不清楚。在这项研究中，我们使用 CUT&RUN 技术研究了小鼠着床前胚胎中 CTCF 的占据情况。我们的研究结果表明，CTCF 在合子基因组激活（ZGA）之前就开始与基因组结合，并且偏爱 CTCF 锚定的染色质环。尽管大多数 CTCF 占据情况保持一致，但我们发现了一组特定的结合位点，这些结合位点富含小鼠特异性短散在元件（SINE）家族 B2，仅局限于卵裂阶段。值得注意的是，我们发现神经保护蛋白 ADNP 拮抗了 CTCF 在 SINE B2 衍生的 CTCF 结合位点上的稳定结合。在合子中敲除 导致 CTCF 结合信号恢复受损、H3K9me3 沉积失败以及 SINE B2 在从桑葚胚到囊胚的转变过程中转录去抑制，这进一步导致胚胎在着床周围的细胞分化出现错误。我们的分析强调了 ADNP 依赖性在着床前胚胎细胞分化过程中对 CTCF 结合的限制。此外，我们的研究结果揭示了转座元件（TEs）在促进遗传创新和积极塑造哺乳动物特有的早期胚胎发育过程中的功能重要性。
