Major evolutionary transitions are enigmas,and the most notable enigma is between invertebrates and vertebrates,with numerous spectacular innovations.To search for the molecular connections involved,we asked whether global epigenetic changes may offer a clue by surveying the inheritance and reprogramming of parental DNA methylation across metazoans.We focused on gametes and early embryos,where the methylomes are known to evolve divergently between fish and mammals.Here,we find that methylome reprogramming during embryogenesis occurs neither in pre-bilaterians such as cnidarians nor in protostomes such as insects,but clearly presents in deuterostomes such as echinoderms and invertebrate chordates,and then becomes more evident in vertebrates.Functional association analysis suggests that DNA methylation reprogramming is associated with development,reproduction and adaptive immunity for vertebrates,but not for invertebrates.Interestingly,the single HOX cluster of invertebrates maintains unmethylated status in all stages examined.In contrast,the multiple HOX clusters show dramatic dynamics ofDNA methylation during vertebrate embryogenesis.Notably,the methylation dynamics of HOX clusters are associated with their spatiotemporal expression in mammals.Our study reveals that DNA methylation reprogramming has evolved dramatically during animal evolution,especially after the evolutionary transitions from invertebrates to vertebrates,and then to mammals.