Dnmt3L and the Establishment of Maternal Genomic Imprints

Abstract

Complementary sets of genes are epigenetically silenced in male and female gametes in a process termed genomic imprinting. The Dnmt3L gene is expressed during gametogenesis at stages where genomic imprints are established. Targeted disruption of Dnmt3L caused azoospermia in homozygous males, and heterozygous progeny of homozygous females died before midgestation. Bisulfite genomic sequencing of DNA from oocytes and embryos showed that removal of Dnmt3L prevented methylation of sequences that are normally maternally methylated. The defect was specific to imprinted regions, and global genome methylation levels were not affected. Lack of maternal methylation imprints in heterozygous embryos derived from homozygous mutant oocytes caused biallelic expression of genes that are normally expressed only from the allele of paternal origin. The key catalytic motifs characteristic of DNA cytosine methyltransferases have been lost from Dnmt3L, and the protein is more likely to act as a regulator of imprint establishment than as a DNA methyltransferase.

Dynamic and reversibility of heterochromatic gene silencing in human disease

“…DNA cytosine-5-methyltrasferase3 Like (DNMT3L) was originally identified by database analysis of the human genome sequences and subsequently a mouse homolog was characterized [26][27][28]. This enzyme lacks amino acids essential for the catalytic activity of methyltransferase.…”

“…DNMT3L is thus unable to perform enzymatic activity. The gene is however essential for the establishment of maternal methylation imprints and for the correct expression of maternally imprinted genes [28]. A mechanism of forming protein complex with DNMT3A and 3B and thus modulating the enzymatic activities of DNMT3A and 3B is probably involved [27,29].…”

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

“…[20][21][22] This enzyme forms a complex with the structurally related, germ-cell-specific cofactor Dnmt3L, which enhances the catalytic activity of Dnmt3a and is important for imprint establishment (Figure 1). 21,[23][24][25] The other de novo methyltransferase Dnmt3b is not involved, except at one particular ICR (see later). Thus, the key proteins in the imprint establishment machinery have been identified, but how they are recruited to specific targets is less clear.…”

Asymétrie des génomes parentaux

“…En effet, les triméthy-lations de la lysine 9 et de la lysine 27 de l'histone H3 sont principalement détectées au niveau du génome maternel et pourraient protéger celui-ci du procesgène de croissance IGF2 et une expression maternelle du gène voisin H19 (Figure 2). Cette méthylation différentielle de l'ADN est acquise dans les cellules germinales via l'enzyme DNMT3A (DNA methyltransferase 3A) en collaboration avec un cofacteur spécifique, DNMT3L (DNA methyltransferase 3-like) (voir ci-dessous) [8,9]. Il est maintenant admis que la méthylation différentielle de l'ADN joue un rôle clé dans le mécanisme de l'empreinte.…”