Genome-wide erasure of CpG methylation occurs along the paternal pronucleus in fertilized oocytes. This process involves an active, replication-independent enzymatic step, which has remained enigmatic. MBD3L1 and MBD3L2 are two mammalian homologues of the methyl-CpG-binding protein genes MBD2 and MBD3 that arose from recent gene duplication events. Expression of Mbd3l1 occurs specifically in haploid male germ cells. Mbd3l2 expression is restricted to metaphase II oocytes and zygotes making both proteins candidates for the zygotic demethylation process. Neither of these genes was able to promote reactivation of a methylation-silenced reporter gene. We created Mbd3l1 and Mbd3l2 knockout mice, which were viable and fertile. We show that demethylation of the paternal pronucleus in Mbd3l1-/- and Mbd3l2-/- mice is identical to that in wild-type controls. These data suggest that Mbd3l1 and Mbd3l2 are not involved in genome-wide demethylation of paternal genomes in mouse zygotes and are dispensable for normal development.
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