| DNA methyltransferase 3 alpha | OKDB#: 2415 |
| Symbols: | DNMT3A | Species: | human | ||
| Synonyms: | TBRS, HESJAS, DNMT3A2, M.HsaIIIA | Locus: | 2p23.3 in Homo sapiens |
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| General Comment |
Genomic imprinting refers to an epigenetic mark that distinguishes parental alleles and results in a monoallelic, parental-specific expression pattern in mammals. Few phenomena in nature depend more on epigenetic mechanisms while at the same time evading them. The alleles of imprinted genes are marked epigenetically at discrete elements termed imprinting control regions (ICRs) with their parental origin in gametes through the use of DNA methylation, at the very least. Imprinted gene expression is subsequently maintained using noncoding RNAs, histone modifications, insulators, and higher-order chromatin structure. Avoidance is manifest when imprinted genes evade the genome-wide reprogramming that occurs after fertilization and remain marked with their parental origin.
(http://genesdev.cshlp.org/content/23/18/2124.full)
The use of conditional deletion alleles of the de novo family of DNA methyltransferase proteins has shown that all of the ICRs tested to date, with one exception, use the de novo DNA methyltransferase DNMT3A and its stimulatory protein, DNMT3L, to confer DNA methylation on the ICRs in the respective germ cells (Bourc'his et al. 2001; Hata et al. 2002; Bourc'his and Bestor 2004; Kaneda et al. 2004).
NCBI Summary: CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase that is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated. [provided by RefSeq, Mar 2016] |
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| General function |
Enzyme, Transferase
, Epigenetic modifications |
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| Comment | |||||
| Cellular localization | Cytoplasmic, Nuclear | ||||
| Comment | DNA methyltransferase expression in the mouse germ line during periods of de novo methylation Lees-Murdock DJ, et al . DNA methyltransferase (DNMT) 3A and DNMT3B are both active de novo DNA methyltransferases required for development, whereas DNMT3L, which has no demonstrable methyltransferase activity, is required for methylation of imprinted genes in the oocyte. We show here that different mechanisms are used to restrict access by these proteins to their targets during germ cell development. Transcriptional control of the Dnmt3l promoter guarantees that message is low or absent except during periods of de novo activity. Use of an alternative promoter at the Dnmt3a locus produces the shorter Dnmt3a2 transcript in the germ line and postimplantation embryo only, whereas alternative splicing of the Dnmt3b transcript ensures that Dnmt3b1 is absent in the male prospermatogonia. Control of subcellular protein localization is a common theme for DNMT3A and DNMT3B, as proteins were seen in the nucleus only when methylation was occurring. These mechanisms converge to ensure that the only time that functional products from each locus are present in the germ cell nuclei is around embryonic day 17.5 in males and after birth in the growing oocytes in females. Developmental Dynamics, 2005. | ||||
| Ovarian function | Early embryo development | ||||
| Comment | Myocardial carnitine transport. Siliprandi N et al. (1987) In mammals, carnitine is synthesized from proteic trimethyllysine in the liver, brain and (in human) kidneys. The hydroxylase catalyzing the last step (deoxycarnitine----carnitine) is missing in the remaining tissues, which are thus entirely dependent on carnitine uptake from the blood. On the basis of experimental evidence, or reasonable assumptions, an interorgan transport of carnitine, carnitine precursors and derivatives is described. In particular, evidence demonstrating a bidirectional exchange between carnitine and deoxycarnitine across cardiac sarcolemma have been provided both in vitro and in vivo experiments. It has been demonstrated that in heart slices carnitine-deoxycarnitine exchange, occurring in a close one to one ratio, is (i) insensitive to both glycolysis and oxidative phosphorylation inhibitors and (ii) sensitive to thiol reagents, such as NEM and Mersalyl. It is assumed that deoxycarnitine is released from muscles into the blood, taken up by the liver, or kidneys, to be hydroxylated to carnitine and the latter returned to the muscles. In vivo evidence for carnitine-deoxycarnitine exchange has been obtained by administering carnitine, or deoxycarnitine, to rats and measuring deoxycarnitine and carnitine, respectively, in different tissues and urine. The results clearly indicate that carnitine administration displaces endogenous deoxycarnitine from tissues and vice versa, thus further supporting the existence of a carnitine-deoxycarnitine exchange process.////////////////// A DNMT3A2-HDAC2 Complex Is Essential for Genomic Imprinting and Genome Integrity in Mouse Oocytes. Ma P et al. (2015) Maternal genomic imprints are established during oogenesis. Histone deacetylases (HDACs) 1 and 2 are required for oocyte development in mouse, but their role in genomic imprinting is unknown. We find that Hdac1:Hdac2(-/-) double-mutant growing oocytes exhibit global DNA hypomethylation and fail to establish imprinting marks for Igf2r, Peg3, and Srnpn. Global hypomethylation correlates with increased retrotransposon expression and double-strand DNA breaks. Nuclear-associated DNMT3A2 is reduced in double-mutant oocytes, and injecting these oocytes with Hdac2 partially restores DNMT3A2 nuclear staining. DNMT3A2 co-immunoprecipitates with HDAC2 in mouse embryonic stem cells. Partial loss of nuclear DNMT3A2 and HDAC2 occurs in Sin3a(-/-) oocytes, which exhibit decreased DNA methylation of imprinting control regions for Igf2r and Srnpn, but not Peg3. These results suggest seminal roles of HDAC1/2 in establishing maternal genomic imprints and maintaining genomic integrity in oocytes mediated in part through a SIN3A complex that interacts with DNMT3A2.////////////////// Mouse Oocyte Methylomes at Base Resolution Reveal Genome-Wide Accumulation of Non-CpG Methylation and Role of DNA Methyltransferases. Shirane K et al. DNA methylation is an epigenetic modification that plays a crucial role in normal mammalian development, retrotransposon silencing, and cellular reprogramming. Although methylation mainly occurs on the cytosine in a CG site, non-CG methylation is prevalent in pluripotent stem cells, brain, and oocytes. We previously identified non-CG methylation in several CG-rich regions in mouse germinal vesicle oocytes (GVOs), but the overall distribution of non-CG methylation and the enzymes responsible for this modification are unknown. Using amplification-free whole-genome bisulfite sequencing, which can be used with minute amounts of DNA, we constructed the base-resolution methylome maps of GVOs, non-growing oocytes (NGOs), and mutant GVOs lacking the DNA methyltransferase Dnmt1, Dnmt3a, Dnmt3b, or Dnmt3L. We found that nearly two-thirds of all methylcytosines occur in a non-CG context in GVOs. The distribution of non-CG methylation closely resembled that of CG methylation throughout the genome and showed clear enrichment in gene bodies. Compared to NGOs, GVOs were over four times more methylated at non-CG sites, indicating that non-CG methylation accumulates during oocyte growth. Lack of Dnmt3a or Dnmt3L resulted in a global reduction in both CG and non-CG methylation, showing that non-CG methylation depends on the Dnmt3a-Dnmt3L complex. Dnmt3b was dispensable. Of note, lack of Dnmt1 resulted in a slight decrease in CG methylation, suggesting that this maintenance enzyme plays a role in non-dividing oocytes. Dnmt1 may act on CG sites that remain hemimethylated in the de novo methylation process. Our results provide a basis for understanding the mechanisms and significance of non-CG methylation in mammalian oocytes. Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Smallwood SA et al. Elucidating how and to what extent CpG islands (CGIs) are methylated in germ cells is essential to understand genomic imprinting and epigenetic reprogramming. Here we present, to our knowledge, the first integrated epigenomic analysis of mammalian oocytes, identifying over a thousand CGIs methylated in mature oocytes. We show that these CGIs depend on DNMT3A and DNMT3L but are not distinct at the sequence level, including in CpG periodicity. They are preferentially located within active transcription units and are relatively depleted in H3K4me3, supporting a general transcription-dependent mechanism of methylation. Very few methylated CGIs are fully protected from post-fertilization reprogramming but, notably, the majority show incomplete demethylation in embryonic day (E) 3.5 blastocysts. Our study shows that CGI methylation in gametes is not entirely related to genomic imprinting but is a strong factor in determining methylation status in preimplantation embryos, suggesting a need to reassess mechanisms of post-fertilization demethylation. Stochastic imprinting in the progeny of Dnmt3L-/- females Arnaud P, et al . The cis-acting regulatory sequences of imprinted genes are subject to germline-specific epigenetic modifications, the imprints, so that this class of genes is exclusively expressed from either the paternal or the maternal allele in offspring. How genes are differentially marked in the germlines remains largely to be elucidated. Although the exact nature of the mark is not fully known, DNA methylation (at differentially methylated regions, DMRs) appears to be a major, functional, component. Recent data in mice indicate that Dnmt3a, an enzyme with de novo DNA methyltransferase activity, and the related protein Dnmt3L are required for methylation of imprinted loci in germ cells. Maternal methylation imprints, in particular, are strictly dependent upon the presence of Dnmt3L. Here we show that, unexpectedly, methylation imprints can be present in some progeny of Dnmt3L-/- females. This incomplete penetrance of the effect of Dnmt3L deficiency in oocytes is neither embryo nor locus specific, but stochastic. We establish that, when it occurs, methylation is present in both embryo and extra-embryonic tissues and results in a functional imprint. This suggests that this maternal methylation is inherited, directly or indirectly, from the gamete. Our results indicate that in the absence of Dnmt3L, factors such as Dnmt3a and possibly others, can act alone to mark individual DMRs. However, establishment of appropriate maternal imprints at all loci does require a combination of all factors. This observation can provide a basis to understand mechanisms involved in some sporadic cases of imprinting related diseases and polymorphic imprinting in human. | ||||
| Expression regulated by | |||||
| Comment | |||||
| Ovarian localization | Primordial Germ Cell, Oocyte, Granulosa | ||||
| Comment | Imprinted genes are differentially marked during germ cell development to allow for their eventual parent-of-origin specific expression. A subset of imprinted genes becomes methylated during oocyte growth in both mouse and human. However the timing and mechanisms of methylation acquisition are unknown. Lucifero et al examined the methylation of the Snrpn, Igf2r, Peg1 and Peg3 differentially methylated regions in postnatal growing mouse oocytes. Our findings indicate that methylation was acquired asynchronously at these different genes. Further analysis of Snrpn DMR1 revealed that parental alleles retain an epigenetic memory of their origin as the two alleles were recognized in a parental-specific manner in the absence of DNA methylation. In addition, we show that methylation acquisition was likely related to oocyte diameter and coincided with the accumulation of Dnmt3a, Dnmt3b and Dnmt3L transcripts. Methylation of the repetitive retroviral-like intracisternal A particle also occurred during this same window of oocyte growth. These findings contribute to our understanding of the epigenetic mechanisms underlying imprint acquisition during female germ cell development and have implications for the practice of assisted reproductive technologies. DNA Methylation and Histone Modifications Are Associated with Repression of the Inhibin a Promoter in the Rat Corpus Luteum. Meldi KM et al. The transition from follicle to corpus luteum after ovulation is associated with profound morphological and functional changes and is accompanied by corresponding changes in gene expression. The gene encoding the a subunit of the dimeric reproductive hormone inhibin is maximally expressed in the granulosa cells of the preovulatory follicle, is rapidly repressed by the ovulatory LH surge, and is expressed at only very low levels in the corpus luteum. Although previous studies have identified transient repressors of inhibin a gene transcription, little is known about how this repression is maintained in the corpus luteum. This study examines the role of epigenetic changes, including DNA methylation and histone modification, in silencing of inhibin a gene expression. Bisulfite sequencing reveals that methylation of the inhibin a proximal promoter is low in preovulatory and ovulatory follicles but is elevated in the corpus luteum. Increased methylation during luteinization is observed within the cAMP response element in the promoter, and EMSA demonstrate that methylation of this site inhibits cAMP response element binding protein binding in vitro. Chromatin immunoprecipitation reveals that repressive histone marks H3K9 and H3K27 trimethylation are increased on the inhibin a promoter in primary luteal cells, whereas the activation mark H3K4 trimethylation is decreased. The changes in histone modification precede the alterations in DNA methylation, suggesting that they facilitate the recruitment of DNA methyltransferases. We show that the DNA methyltransferase DNMT3a is present in the ovary and in luteal cells when the inhibin a promoter becomes methylated and observe recruitment of DNMT3a to the inhibin promoter during luteinization. | ||||
| Follicle stages | |||||
| Comment | Sex-specific windows for high mRNA expression of DNA methyltransferases 1 and 3A and methyl-CpG-binding domain proteins 2 and 4 in human fetal gonads. Galetzka D et al. DNA methyltransferases (DNMTs) and 5-methyl-CpG-binding domain proteins (MBDs) are involved in the acquisition of parent-specific epigenetic modifications in human male and female germ cells. Reverse Northern blot analyses demonstrated sex-specific differences in mRNA expression for the maintenance DNMT1 and the de novo DNMT3A in developing testis and ovary. In fetal testis DNMT1 and DNMT3A expression peaked in mitotically arrested spermatogonia around 21 weeks gestation. In fetal ovary transcriptional upregulation of DNMT1 and DNMT3A occurred during a very brief period at 16 weeks gestation, when the oocytes proceeded through meiotic prophase. Fetal gonads showed several fold higher DNMT3A expression levels than fetal brain and adult tissues. The most abundant DNMT3A isoform in fetal testis and ovary was DNMT3A2, whereas in all other analyzed tissues DNMT3A1 predominated. The catalytically inactive DNMT3A3 isoform was also present at relatively high levels in developing gonads and may perform a regulatory function(s). In both male and female fetal gonads expression of genes for MBD2 and MBD4, which may be implicated in chromatin remodeling of methylated genomic DNA sequences, was tightly linked to DNMT expression. We propose that the sex-specific time windows for concomitant upregulation of DNMT1, DNMT3A, MBD2, and MBD4 are associated with prenatal remethylation of the human male and female germ line. Mol. Reprod. Dev. (c) 2006 Wiley-Liss, Inc. | ||||
| Phenotypes | |||||
| Mutations |
4 mutations
Species: mouse
Species: mouse
Species: mouse
Species: mouse
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | March 10, 2004, 8:29 p.m. | by: |
hsueh email:
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| last update: | June 2, 2021, 9:18 a.m. | by: | hsueh email: |
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