Active demethylation of the paternal genome in the mouse zygote

Abstract

DNA methylation is essential for the control of a number of biological mechanisms in mammals [1]. Mammalian development is accompanied by two major waves of genome-wide demethylation and remethylation: one during germ-cell development and the other after fertilisation [2] [3] [4] [5] [6] [7]. Most previous studies have suggested that the genome-wide demethylation observed after fertilisation occurs passively, that is, by the lack of maintenance methylation following DNA replication and cell division [6] [7], although one other study has reported that replication-independent demethylation may also occur during early embryogenesis [8]. Here, we report that genes that are highly methylated in sperm are rapidly demethylated in the zygote only hours after fertilisation, before the first round of DNA replication commences. By contrast, the oocyte-derived maternal alleles are unaffected by this reprogramming. They either remain methylated after fertilisation or become further methylated de novo. These results provide the first direct evidence for active demethylation of single-copy genes in the mammalian zygote and, moreover, reveal a striking asymmetry in epigenetic methylation reprogramming. Whereas paternally (sperm)-derived sequences are exposed to putative active demethylases in the oocyte cytoplasm, maternally (oocyte)-derived sequences are protected from this reaction. These results, whose generality is supported by findings of Mayer et al. [9], have important implications for the establishment of biparental genetic totipotency after fertilisation, the establishment and maintenance of genomic imprinting, and the reprogramming of somatic cells during cloning.

Reprogramming of genome function through epigenetic inheritance

“…During the initial 0-5 h.p.f., the parental genomes exhibit dramatic epigenetic differences. The paternal genome undergoes marked demethylation while the maternal genome, which contains most of the methylation marks associated with imprints, undergoes further de novo methylation 11,12,47 . Species where imprinting is unknown do not show such differential methylation of parental genomes during early development.…”

“…Loss of function of either of the two genes results in the loss of germ cell lineage in worms. Genome-wide demethylation is also observed in PGCs and in the paternal genome in the zygote 11,12,56 , although it is important to note that whereas the imprints are erased in PGCs, this is not the case during embryonic development.…”

“…Both the erasure of DNA methylation and the initiation of new epigenetic modifications seem possible, based on studies on the zygote. The imprints have the potential to survive during reprogramming of somatic nuclei to totipotency 11,12,47,58 , but are occasionally erased as well 57 .…”

Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals

“…14,15 This important pathway for active DNA demethylation has been thought to be involved in a number of prominent biological processes. 5,6,10,11 Early and recent studies suggested that active and replication-independent DNA demethylation might be a rapid process. 10,11 The radically altered methylation, as observed in replication-independent demethylation of the paternal genome in zygotes, may complete within hours.…”

Gradual development of a genome‐wide H3‐K9 trimethylation pattern in paternally derived pig pronucleus

“…Pre-existing 5-methylcytosines (5-MeCs) of the incoming sperm genome are removed in the oocyte cytoplasm in mice Oswald et al, 2000;Santos et al, 2002). Active demethylation of paternally derived genome has been asserted to occur by showing asymmetric methylation states between the male and the female pronuclei in rat, cow, and pig zygotes .…”