Figure 8.

Full landscape of extrachromosomal circular DNA in fetal growth restriction. (A) Factors promoting the formation of eccDNAs/ecDNAs in the placenta. Oxidative stress, apoptosis, aging, and immune imbalance at the maternal-fetal interface (such dNK cells, macrophage T cells, B cells, etc.) deteriorate chromosome fragmentation and deletion of gene fragments in trophoblast. (B) EccDNAs/ecDNAs of different ontogenetic origins in the placenta and potential mechanisms of formation. (1) Different DNA fragments shed from the same chromosome form multiple cycles by microhomologous recombination. (2) Different DNA fragments shed from different chromosomes are integrated into a cycle by microhomologous recombination.(3) Virus-derived DNA fragments integrate with human chromosomally shed DNA fragments forming cycles. (C) Potential functions of eccDNAs/ecDNAs in the placenta. (1) Circular DNA lacks centromere, which inherits genes unequally into offspring cells promoting disease heterogeneity. (2) Effect of altered topology due to cyclization, or promotion of (enhancer linked to promoter topology) gene transcriptional enhancement by sequence rearrangement on the cycle. (3) miRNA or siRNA is produced by eccDNA and interacts with mRNA to suppress gene expression. (4) Cycles carrying enhancers or repressors are chimerized into the genomes of different linear DNAs, forming chromosomal recombination that enhances or represses gene expression. (5) Influence genes expression through network and cross-talk with ncRNAs. (D) Placental dysfunction leading to FGR.