Alternative titles; symbols
HGNC Approved Gene Symbol: DNMT1
SNOMEDCT: 860812002;
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:10,133,346-10,194,953 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant | 604121 | Autosomal dominant | 3 |
| Neuropathy, hereditary sensory, type IE | 614116 | Autosomal dominant | 3 |
DNA (cytosine-5)-methyltransferases (DNMTs; EC 2.1.1.37), such as DNMT1, maintain patterns of methylated cytosine residues in the mammalian genome. Genomic methylation patterns are reshaped during gametogenesis and early development and undergo programmed alterations during cellular differentiation. Methylation patterns are responsible for the repression of parasitic sequence elements and the expression status of genes subject to genomic imprinting and X inactivation. Faithful maintenance of methylation patterns is required for normal mammalian development, and aberrant methylation patterns are associated with certain human tumors and developmental abnormalities (Yoder et al., 1996).
Bestor et al. (1988) showed that murine Dnmt cDNA encodes a C-terminal domain of 500 amino acids that is closely related to the bacterial type II restriction methyltransferases that form 5-methylcytosine. This catalytic domain is linked to an N-terminal domain of 1,000 amino acids that was predicted by Bestor (1990) to have regulatory functions.
El-Deiry et al. (1991) cloned a portion of the human DNA methyltransferase gene. Expression of the gene was low in normal human cells, increased significantly in virally transformed cells, and was elevated in human cancer cells. The increases paralleled the progression of colonic neoplasms.
Yen et al. (1992) isolated overlapping cDNA clones encoding a 5,194-bp transcript for human DNMT. It shows 80% homology at the nucleotide level and 74% identity at the amino acid level to the Dnmt cDNA cloned from mouse cells.
Tucker et al. (1996) showed that the published Dnmt sequence encodes an N-terminally truncated protein. This truncated protein was tolerated only at very low levels when stably expressed in embryonic stem cells. However, normal expression levels were obtained with constructs containing an ORF with a coding capacity of up to 171 amino acids upstream of the start site previously defined by Rouleau et al. (1992). Protein encoded by these constructs comigrated in SDS-PAGE with the endogenous enzyme.
Independently, Yoder et al. (1996) investigated the organization of coding sequences at the 5-prime end of the murine and human DNMT genes and found that the ORF is longer than previously suspected. Expression of the complete ORF by in vitro transcription/translation and by transfection of expression constructs into COS-7 cells resulted in the production of an active enzyme of the same apparent mass as the endogenous protein, while translation from the second in-frame ATG codon produced a slightly smaller but fully active protein. They showed that the previously described promoter element (Rouleau et al., 1992) lies in an intron that is more than 5 kb downstream of the transcription start sites.
A DNMT1 enzyme is thought to be responsible for most of the maintenance as well as the de novo methylation activities occurring in the somatic cells of vertebrates. Several minor species of mammalian DNA (cytosine-5) methyltransferase have been identified and cloned. These are designated DNMT2 (602478), DNMT3A (602769), and DNMT3B (602900). Hsu et al. (1999) reported the incidental discovery of a second major form of CpG MTase that was abundantly expressed in different human somatic tissues and cell lines. The mRNA coding for this CpG MTase, which appeared to originate from alternative splicing of the primary DNMT1 transcript, inserts an additional 16 amino acids, encoded by a human Alu family repeat, between exons 4 and 5 of the DNMT1 protein. Hsu et al. (1999) found that the 48-nucleotide exon sequence is derived from the first, or the most upstream, copy of a set of 7 different Alu repeats located in intron 4. The ratios of expression of this mRNA to the expression of the previously known, shorter DNMT1 mRNA species, as estimated by semiquantitative reverse transcription-PCR analysis, ranged from two-thirds to three-sevenths. Hsu et al. (1999) suggested that the originally described form be named DNMT1A and the recently discovered form DNMT1B. Analysis of chimpanzee cells suggested that 2 abundant forms of somatic CpG MTase are conserved in the higher primates.
Bonfils et al. (2000) independently identified and cloned the DNMT1B splice variant. Using an RNase protection assay, they estimated lower levels of expression of DNMT1B compared with full-length DNMT1 in several cancer cell lines and in normal fibroblasts; levels ranged from 6% in a human bladder cancer cell line to 20 to 30% in a breast cancer cell line. Western blot analysis revealed that DNMT1B represents 2 to 5% of the total DNMT1 protein and is therefore a minor DNA methyltransferase isoform.
Using 5-prime RACE, Mertineit et al. (1998) identified 2 splice variants of mouse Dnmt1, one that was uniquely expressed in pachytene spermatocytes, and another that was uniquely expressed in growing pre- and postnatal oocytes. These transcripts contain alternative first exons compared with somatic Dnmt1 mRNA. The male sex-specific transcript contains several small upstream ORFs, and Mertineit et al. (1998) found that it was not actively translated and interfered with Dnmt1 translation during the prolonged crossing-over stage of male meiosis. The female sex-specific transcript encodes a highly active methyltransferase with an N-terminal truncation compared with somatic Dnmt1. Immunohistochemical analysis of testis detected high levels of nuclear Dnmt1 at all stages of sperm development except in pachytene spermatocytes, which was concurrent with high expression of the sex-specific transcript. Growing oocytes, but not nongrowing oocytes, showed intense Dnmt1 nuclear staining and substantial cytoplasmic staining. Dnmt1 localization became progressively more cytoplasmic during growth, and at the time of ovulation, all Dnmt1 staining was cytoplasmic and was associated with the oocyte cortex. Mature oocytes and early preimplantation embryos also showed high cytoplasmic Dnmt1 expression. After implantation, Dnmt1 again became nuclear.
Using Northern blot analysis, Xie et al. (1999) detected ubiquitous DNMT1 expression, with highest levels in testis, followed by placenta, spleen, bone marrow, and peripheral blood leukocytes.
Robertson et al. (1999) detected DNMT1 expression in all adult and fetal tissues examined by Northern blot analysis except small intestine, and several transcripts were present in some tissues. Expression was highest in 24-week fetal tissues, and it was extremely high in fetal liver. Semiquantitative RT-PCR confirmed ubiquitous DNMT1 expression, including in small intestine. Expression of DNMT1, DNMT3A, and DNMT3B appeared to be coregulated in most tissues, since they frequently had a similar pattern of expression.
Using reverse RNA dot-blot analysis, Galetzka et al. (2007) found that DNMT1 and DNMT3A expression peaked in mitotically arrested spermatogonia in human fetal testis around 21 weeks' gestation. In fetal ovary, upregulation of DNMT1 and DNMT3A mRNA occurred during a very brief period at 16 weeks' gestation, when oocytes proceeded through meiotic prophase. In both male and female fetal gonads, expression of MBD2 (603547) and MBD4 (603574) was tightly linked to DNMT expression, suggesting that concomitant upregulation of DNMT1, DNMT3A, MBD2, and MBD4 is associated with prenatal remethylation in male and female germlines.
In their Figure 1, Bigey et al. (2000) showed that the DNMT1 gene contains at least 37 exons. Bigey et al. (2000) identified 4 clusters of transcription initiation sites, which they called P1 through P4, in DNMT1. The major cluster, P1, is located within a CG-rich region in exon 1. The minor clusters, P2, P3, and P4, are located within CG-poor regions in exons 2, 3, and 4, respectively. Functional analysis showed that each cluster is associated with independent upstream promoter and enhancer sequences. P2, P3, and P4 are each associated with an upstream JUN (165160) enhancer. El-Maarri et al. (2009) noted that the DNMT1 gene contains 40 exons.
Mertineit et al. (1998) identified sex-specific first exons in the mouse Dnmt1 gene 5-prime to the first exon used by somatic Dnmt1. The spermatocyte-specific exon, exon 1s, contains a promoter region and introduces a number of small upstream ORFs. The ovary-specific exon, exon 1o, causes translation to begin at an ATG in exon 4 and also introduces small upstream ORFs.
El-Deiry et al. (1991) localized the DNMT1 gene to chromosome 19 by analysis of a panel of human-hamster somatic cell hybrid DNAs. By fluorescence in situ hybridization, Yen et al. (1992) mapped the human DNMT gene to 19p13.3-p13.2.
Crystal Structure
Song et al. (2011) solved structures of mouse and human DNMT1 composed of CXXC, tandem bromo-adjacent homology (BAH1/2), and methyltransferase domains bound to DNA-containing unmethylated CpG sites. The CXXC specifically binds to unmethylated CpG dinucleotide and positions the CXXC-BAH1 linker between the DNA and the active site of DNMT1, preventing de novo methylation. In addition, a loop projecting from BAH2 interacts with the target recognition domain (TRD) of the methyltransferase, stabilizing the TRD in a retracted position and preventing it from inserting into the DNA major groove.
Song et al. (2012) reported on the crystal structure of a productive covalent mouse DNMT1(731-1602)-DNA complex containing a central hemimethylated CpG site. The methyl group of methylcytosine is positioned within a shallow hydrophobic concave surface, whereas the cytosine on the target strand is looped out and covalently anchored within the catalytic pocket. The DNA is distorted at the hemimethylated CpG step, with side chains from catalytic and recognition loops inserting through both grooves to fill an intercalation-type cavity associated with a dual base flip-out on partner strands. Song et al. (2012) concluded that structural and biochemical data established how a combination of active and autoinhibitory mechanisms ensures the high fidelity of DNMT1-mediated maintenance DNA methylation.
Tucker et al. (1996) noted that previous attempts to express functional DNMT in cells transfected with available DNMT cDNAs, which encode an N-terminally truncated protein, have been unsuccessful. They found that expression of DNMT protein containing the entire N-terminal sequence restored methylation activity in transfected cells. This was shown by functional rescue of DNMT mutant embryonic stem cells that contained highly demethylated genomic DNA and failed to differentiate normally. When transfected with the DNMT minigene construct, the genomic DNA became remethylated and the cells regained the capacity to form teratomas displaying a wide variety of differentiated cell types. The results of Tucker et al. (1996) defined an N-terminal domain of the mammalian DNMT enzyme that is crucial for stable expression and function in vivo.
Chuang et al. (1997) analyzed the factors regulating the activity of DNA (cytosine-5)-methyltransferase (symbolized MCMT by them) in methylating newly replicated DNA. They showed that MCMT binds proliferating cell nuclear antigen (PCNA; 176740), an auxiliary factor for DNA replication and repair. Binding of PCNA requires amino acids 163 to 174 of MCMT, occurs in intact cells at foci of newly replicated DNA, and does not alter MCMT activity. They showed that a peptide derived from the cell cycle regulator p21(WAF1) (CDKN1A; 116899) can disrupt the MCMT-PCNA interaction, which suggested to Chuang et al. (1997) that p21(WAF1) may regulate methylation by blocking access of MCMT to PCNA. MCMT and p21(WAF1) may be linked in a regulatory pathway, because the extents of their expression are inversely related in both SV40-transformed and nontransformed cells.
Bonfils et al. (2000) purified full-length DNMT1 and the DNMT1B splice variant, which were expressed as recombinant proteins in insect cells, and compared their cytosine-5 DNA methyltransferase activity. Both proteins had similar Michaelis constants for hemimethylated and nonmethylated DNA, as well as for the cofactor S-adenosyl-L-methionine. The kinetics were also similar to those determined for the murine Dnmt1 enzyme.
Rountree et al. (2000) showed that DNMT1 can establish a repressive transcription complex consisting of DNMT1, the histone deacetylase HDAC2 (605164), and DMAP1 (605077). The noncatalytic amino terminus of DNMT1 binds to HDAC2 and to DMAP1 and can mediate transcriptional repression. DMAP1 is targeted to replication foci through interaction with the far N terminus of DNMT1 throughout S phase, whereas HDAC2 joins DNMT1 and DMAP1 only during late S phase, providing a platform for how histones may become deacetylated in heterochromatin following replication. Thus, DNMT1 not only maintains DNA methylation, but also may directly target, in a heritable manner, transcriptionally repressive chromatin to the genome during DNA replication.
DNMT1 is responsible for cytosine methylation in mammals and has a role in gene silencing. DNA methylation represses genes partly by recruitment of the methyl-CpG-binding protein MECP2 (300005), which in turn recruits a histone deacetylase activity. Fuks et al. (2000) showed that DNMT1 is itself associated with histone deacetylase activity in vivo. Consistent with this association, they found that one of the known histone deacetylases, HDAC1 (601241), has the ability to bind Dnmt1 and can purify methyltransferase activity from nuclear extracts. They identified a transcriptional repression domain in DNMT1 that functions, at least partly, by recruiting histone deacetylase activity and shows homology to the repressor domain of the trithorax-related protein HRX (also known as MLL and ALL1; 159555). The observations showed a more direct connection between DNA methylation and histone deacetylation than had previously been considered. Fuks et al. (2000) suggested that the process of DNA methylation, mediated by DNMT1, may depend on or generate an altered chromatin state via histone deacetylase activity.
Methylation of CpG islands is associated with transcriptional silencing and the formation of nuclease-resistant chromatin structures enriched in hypoacetylated histones. Methyl-CpG-binding proteins, such as MeCP2, provide a link between methylated DNA and hypoacetylated histones by recruiting histone deacetylase. Robertson et al. (2000) studied the mechanisms establishing methylation patterns. They investigated whether DNA methylation is always causal for the assembly of repressive chromatin or whether features of transcriptionally silent chromatin might target methyltransferase. Mammalian DNA methyltransferases show little sequence specificity in vitro, yet methylation can be targeted in vivo within chromosomes to repetitive elements, centromeres, and imprinted loci. This targeting is frequently disrupted in tumor cells, resulting in the improper silencing of tumor suppressor genes associated with CpG islands. Robertson et al. (2000) showed that the predominant mammalian DNA methyltransferase, DNMT1, copurifies with RB1 (614041), E2F1 (189971), and HDAC1, and that DNMT1 cooperates with RB1 to repress transcription from promoters containing E2F-binding sites. These results established a link between DNA methylation, histone deacetylase, and sequence-specific DNA binding activity, as well as a growth regulatory pathway that is disrupted in nearly all cancer cells.
DNMT1 lacks a methyl-CpG-binding domain, raising questions as to how it is recruited to hemimethylated DNA and how it replicates the methylation pattern during cell division. By expressing rodent cDNAs in human embryonic kidney cells, Kimura and Shiota (2003) showed that Dnmt1 interacted directly with Mecp2. Dnmt1 formed complexes with HDACs as well as with Mecp2, but Mecp2-interacting Dnmt1 did not bind Hdac1. Mecp2 could form complexes with hemimethylated and fully methylated DNA. Immunoprecipitated Mecp2 complexes showed DNA methyltransferase activity to hemimethylated DNA. Kimura and Shiota (2003) concluded that DNMT1 associates with MECP2 in order to perform maintenance methylation during cell division.
Rhee et al. (2000) disrupted the DNMT1 gene through homologous recombination targeting exons 3, 4, and 5 in HCT116 human colorectal carcinoma cells. Cells lacking DNMT1 exhibited markedly decreased cellular DNA methyltransferase activity, but there was only a 20% decrease in overall genomic methylation. Although juxtacentromeric satellites became significantly demethylated, most of the loci that Rhee et al. (2000) analyzed, including the tumor suppressor gene p16(INK4A), remained fully methylated and silenced. These results indicated that DNMT1 has an unsuspected degree of regional specificity in human cells and that methylating activities other than DNMT1 can maintain the methylation of most of the genome.
Rhee et al. (2002) disrupted the human DNMT3B gene (602900) in HCT116 cells. This deletion reduced global DNA methylation by less than 3%. However, genetic disruption of both DNMT1 and DNMT3B nearly eliminated methyltransferase activity and reduced genomic DNA methylation by greater than 95%. These marked changes resulted in demethylation of repeated sequences, loss of insulin-like growth factor II imprinting, abrogation of silencing of the tumor suppressor gene p16(INK4), and growth suppression. Rhee et al. (2002) concluded that DNMT1 and DNMT3B cooperatively maintain DNA methylation and gene silencing in human cancer cells and that such methylation is essential for optimal neoplastic proliferation.
Paz et al. (2003) searched for hypermethylated CpG islands in HCT116 cells in which both DNMT1 and DNMT3B had been genetically disrupted (DKO cells). The authors found that DKO cells, but not the single DNMT1 or DNMT3B knockouts, had a massive loss of hypermethylated CpG islands that induced reactivation of the contiguous genes. A substantial number of these CpG island-associated genes had potentially important roles in tumorigenesis. For other genes whose role in transformation was not characterized, their reintroduction in DKO cells inhibited colony formation.
HCT116 cells with homozygous deletion of exons 3 to 5 of DNMT1 (MT1KO cells) show only a 20% reduction in global genomic methylation levels and almost no loss of methylation at CpG islands (Rhee et al., 2000). Spada et al. (2007) found that alternative splicing between exons 2 and 7 of the DNMT1 gene bypasses the knockout cassette in MT1KO cells, resulting in expression of a mutant DNMT1 protein lacking the PCNA-binding domain, but not the methyltransferase domains. Western blot analysis detected the mutant DNMT1 protein at an apparent molecular mass of 160 kD, rather than the wildtype 180 kD. A mechanism-based trap assay showed that this truncated DNMT1 protein displayed only 2-fold reduced postreplicative DNA methylation maintenance activity in vivo. Knockdown of this truncated DNMT1 in MT1KO cells by RNA interference resulted in global genomic hypomethylation and cell death. Spada et al. (2007) concluded that DNMT1 is essential for maintenance of DNA methylation and that interaction of DNMT1 with the replication machinery is not strictly necessary for maintenance of DNA methylation, but improves its efficiency.
Using coimmunoprecipitation of recombinant proteins expressed in insect cells and COS-7 cells, Kim et al. (2002) identified interaction between DNMT1, DNMT3A, and DNMT3B. By mutation analysis, they localized the interacting domains to the N termini of the proteins. Immunocytochemical staining revealed mostly nuclear colocalization of fluorescence-labeled proteins, except for DNMT3A, which was found either exclusively in the cytoplasm or in both the cytoplasm and nucleus. In vivo coexpression of DNMT1 and DNMT3A and/or DNMT3B led to methylation spreading in the genome, suggesting cooperation between them.
Transcriptional silencing by CpG island methylation is a prevalent mechanism of tumor-suppressor gene suppression in cancers. Robert et al. (2003) used a combination of genetic (antisense and siRNA) and pharmacologic (5-aza-2-prime-deoxycytidine) inhibitors of DNA methyltransferases to study the contribution of the several DNMT isotypes to cancer cell methylation. Selective depletion of DNMT1 using either antisense or siRNA resulted in lower cellular maintenance methyltransferase activity, global and gene-specific T methylation, and reexpression of tumor suppressor genes in human cancer cells. Specific depletion of DNMT1 but not DNMT3A and DNMT3B markedly potentiated the ability of 5-aza-2-prime-deoxycytodine to reactivate silenced tumor suppressor genes, indicating that inhibition of DNMT1 function is the principal means by which the agent reactivates genes. These results indicated that DNMT1 is necessary and sufficient to maintain global methylation and aberrant CpG island methylation in human cancer cells.
Chen et al. (2007) examined the role of DNMT1 in human cancer cells. Using homologous recombination, they generated a DNMT1 conditional allele in HCT116 cells in which several exons encoding the catalytic domain were flanked by loxP sites. Cre recombinase-mediated disruption of this allele resulted in hemimethylation of approximately 20% of CpG-CpG dyads in the genome, coupled with activation of the G2/M checkpoint, leading to arrest in the G2 phase of the cell cycle. Although cells gradually escaped from this arrest, they showed severe mitotic defects and underwent cell death either during mitosis or after arresting in a tetraploid G1 state. The results indicated that DNMT1 is required for faithful maintenance of DNA methylation patterns in human cancer cells and is essential for their proliferation and survival.
Guidotti et al. (2000) found a downregulation of reelin (600514) and glutamate decarboxylase-1 (GAD1; 605363) mRNAs in GABAergic cortical interneurons in schizophrenia postmortem brains, suggesting a decrease in the availability of GABA and reelin in schizophrenia cortex. Using in situ hybridization of DNMT1 mRNA, Veldic et al. (2004) showed that the expression of this mRNA is increased in cortical GABAergic interneurons but not in pyramidal neurons of schizophrenia brains. The findings were consistent with the hypothesis that the increase of DNMT1 expression in telencephalic GABAergic interneurons of schizophrenia patients causes a promoter hypermethylation of reelin and GAD67 and perhaps of other genes expressed in these interneurons. It was difficult to determine whether this dysfunction of GABAergic neurons detected in schizophrenia is responsible for the disease or is a consequence of the disorder. Although they could not differentiate between those 2 alternatives, it was important to consider that up to that time a molecular pathology of cortical GABAergic neurons was the most consistent finding associated with schizophrenia morbidity.
Veldic et al. (2005) found increased levels of DNMT1 mRNA-positive GABAergic interneurons in Broca area 9 in 19 patients with schizophrenia and 14 patients with bipolar disorder with psychosis compared with 5 bipolar patients without psychosis and 26 nonpsychiatric individuals. The effect was layer-specific, with significant differences between the 2 groups noted only in layers I, II, and IV. The increase in DNMT1 mRNA was associated with a significant decrease of GAD67 mRNA-positive neurons. The increase in DNMT1 expression was not related to postmortem interval, antipsychotic medication, or smoking; however, a subset of patients receiving a combination of antipsychotic medication and valproate, which inhibits histone deacetylases and affects DNA methylation, showed no increase in DNMT1 expression.
Guo et al. (2004) exploited the high rate of mitotic recombination in Bloom syndrome protein (Blm; 604610)-deficient embryonic stem cells to generate a genomewide library of homozygous mutant cells from heterozygous mutations induced with a revertible gene trap retrovirus. Guo et al. (2004) screened this library for cells with defects in DNA mismatch repair (MMR), a system that detects and repairs base-base mismatches. They demonstrated the recovery of cells with homozygous mutations in known and novel mismatch repair genes. Guo et al. (2004) identified DNMT1 as a novel MMR gene and confirmed that Dnmt1-deficient embryonic stem cells exhibit microsatellite instability, providing a mechanistic explanation for the role of DNMT1 in cancer.
The genome undergoes multiple rounds of methylation and demethylation during embryogenesis, but methylation of the retrotransposon intracisternal A-type particle (IAP) is maintained to maintain its silencing. Gaudet et al. (2004) found that the shorter oocyte-specific Dnmt1 isoform maintained IAP methylation in the cleavage-stage mouse embryo. The longer isoform found in male gametes and somatic cells maintained IAP methylation after implantation.
In order to clarify the role of DAXX (603186) in IFNA (147660)/IFNB (147640)-mediated suppression of B-cell development and apoptosis, Muromoto et al. (2004) used a yeast 2-hybrid screen and identified DMAP1 as a DAXX-interacting protein. Immunoprecipitation and Western blot analysis with DAXX mutants showed that the N terminus of DAXX interacts with the C terminus of DMAP. Immunoblot analysis and confocal microscopy demonstrated that the DAXX-DMAP complex interacts with DNMT1 in the nucleus. Transient expression of DAXX or DMAP1 caused repression of glucocorticoid receptor (GCCR; 138040)-mediated transcription. Muromoto et al. (2004) concluded that the linkage between DAXX and DNMT1 forms an efficient transcription repression complex in the nucleus.
Esteve et al. (2005) found that DNMT1 bound p53 (191170) and the 2 proteins colocalized in the nucleus of human colon carcinoma cell lines. DNMT1 and p53 cooperated in the methylation and repression of endogenous survivin (BIRC5; 603352), a target gene containing p53 binding sites in the promoter region.
T-cell lymphomas lose expression of SHP1 (PTPN6; 176883) due to DNA methylation of its promoter. Zhang et al. (2005) demonstrated that malignant T cells expressed DNMT1 and that STAT3 (102582) could bind sites in the SHP1 promoter in vitro. STAT3, DNMT1, and HDAC1 formed complexes and bound to the SHP1 promoter in vivo. Antisense DNMT1 and STAT3 siRNA induced DNA demethylation in malignant T cells and expression of SHP1. Zhang et al. (2005) concluded that STAT3 may transform cells by inducing epigenetic silencing of SHP1 in cooperation with DNMT1 and HDAC1.
Vire et al. (2006) showed that the silencing pathways of the polycomb group (PcG) and DNA methyltransferases systems are mechanically linked. They found that the PcG protein EZH2 (601573) interacts--within the context of the Polycomb repressive complexes 2 and 3 (PRC2/3)--with DNA methyltransferases DNMT1, DNMT3A (602769), and DNMT3B and associates with DNMT activity in vivo. Chromatin immunoprecipitations indicated that binding of DNMTs to several EZH2-repressed genes depends on the presence of EZH2. Furthermore, Vire et al. (2006) showed by bisulfite genomic sequencing that EZH2 is required for DNA methylation of EZH2-target promoters. Vire et al. (2006) concluded that EZH2 serves as a recruitment platform for DNA methyltransferases, thus highlighting a previously unrecognized direct connection between 2 key epigenetic repression systems.
Smallwood et al. (2007) demonstrated that DNMT1 could interact with HP1-alpha (CBX5; 604478), HP1-beta (CBX1; 604511), and HP1-gamma (CBX3; 604477) in a human colon carcinoma cell line, resulting in stimulation of DNMT1 methyltransferase activity. The HP1 proteins were sufficient to target DNMT1 activity in vivo, and HP1-dependent repression required DNMT1. Smallwood et al. (2007) demonstrated that HP1-alpha and HP1-beta were recruited to the survivin promoter in a DNMT1-dependent manner. They concluded that direct interactions between HP1 proteins and DNMT1 mediate silencing of euchromatic genes.
Gazin et al. (2007) performed a genomewide RNA interference (RNAi) screen in Kras (190070)-transformed NIH 3T3 cells and identified 28 genes required for Ras-mediated epigenetic silencing of the proapoptotic Fas gene (TNFRSF6; 134637). At least 9 of these Ras epigenetic silencing effectors (RESEs), including the DNA methyltransferase Dnmt1, were directly associated with specific regions of the Fas promoter in Kras-transformed NIH 3T3 cells but not in untransformed NIH 3T3 cells. RNAi-mediated knockdown of any of the 28 RESEs resulted in failure to recruit Dnmt1 to the Fas promoter, loss of Fas promoter hypermethylation, and derepression of Fas expression. Analysis of 5 other epigenetically repressed genes indicated that Ras directed the silencing of multiple unrelated genes through a largely common pathway. Finally, Gazin et al. (2007) showed that 9 RESEs were required for anchorage-independent growth and tumorigenicity of Kras-transformed NIH 3T3 cells; these 9 genes had not previously been implicated in transformation by Ras. Gazin et al. (2007) concluded that RAS-mediated epigenetic silencing occurs through a specific, complex pathway involving components that are required for maintenance of a fully transformed phenotype.
Bostick et al. (2007) showed that the protein UHRF1 (607990), also known as NP95 in mouse and ICBP90 in human, is required for maintaining DNA methylation. UHRF1 colocalizes with the maintenance DNA methyltransferase protein DNMT1 throughout S phase. UHRF1 appears to tether DNMT1 to chromatin through its direct interaction with DNMT1. Furthermore, UHRF1 contains a methyl DNA binding domain, the SRA (SET- and RING-associated) domain, that shows strong preferential binding to hemimethylated CG sites, the physiologic substrate for DNMT1. Bostick et al. (2007) concluded that UHRF1 may help recruit DNMT1 to hemimethylated DNA to facilitate faithful maintenance of DNA methylation.
Sharif et al. (2007) demonstrated that localization of mouse Np95 to replicating heterochromatin is dependent on the presence of hemimethylated DNA. Np95 forms complexes with Dnmt1 and mediates the loading of Dnmt1 to replicating heterochromatic regions. By using Np95-deficient embryonic stem cells and embryos, Sharif et al. (2007) showed that Np95 is essential in vivo to maintain global and local DNA methylation and to repress transcription of retrotransposons and imprinted genes. Sharif et al. (2007) concluded that the link between hemimethylated DNA, Np95, and Dnmt1 thus establishes key steps of the mechanism for epigenetic inheritance of DNA methylation.
Using ELISA, Balada et al. (2008) determined that the DNA deoxymethylcytosine content of purified CD4 (186940)-positive T cells was lower in patients with systemic lupus erythematosus (SLE; 152700) than in controls. RT-PCR analysis detected no differences in DNMT1, DNMT3A, or DNMT3B transcript levels between SLE patients and controls. However, simultaneous association of low complement counts with lymphopenia, high titers of anti-double-stranded DNA, or a high SLE disease activity index resulted in an increase in at least 1 of the DNMTs. Balada et al. (2008) proposed that patients with active SLE and DNA hypomethylation have increased DNMT mRNA levels.
Wang et al. (2009) demonstrated that LSD1 (609132) is required for gastrulation during mouse embryogenesis. Notably, targeted deletion of the gene encoding LSD1 in embryonic stem cells induces progressive loss of DNA methylation. This loss correlates with a decrease in DNA methyltransferase-1 protein, as a result of reduced Dnmt1 stability. Dnmt1 protein is methylated in vivo, and its methylation is enhanced in the absence of LSD1. Furthermore, Dnmt1 can be methylated by Set7/9 (also known as KMT7, 606594) and demethylated by LSD1 in vitro. Wang et al. (2009) concluded that LSD1 demethylates and stabilizes Dnmt1, thus providing a previously unknown mechanistic link between the histone and DNA methylation systems.
Sen et al. (2010) showed that DNMT1 is essential for epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation, and eventual tissue loss. Genomewide analysis showed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Furthermore, UHRF1, a component of the DNA methylation machinery that targets DNMT1 to hemimethylated DNA, is also necessary to suppress premature differentiation and sustain proliferation. In contrast, Gadd45A (126335) and B (604948), which promote active DNA demethylation, are required for full epidermal differentiation gene induction. Sen et al. (2010) concluded that proteins involved in the dynamic regulation of DNA methylation patterns are required for progenitor maintenance and self-renewal in mammalian somatic tissue.
Di Ruscio et al. (2013) presented data demonstrating that active transcription regulates levels of genomic methylation. They identified a novel nuclear nonpolyadenylated noncoding RNA (ncRNA) arising from the CEBPA (116897) gene locus that is critical in regulating the local DNA methylation profile. They termed this ncRNA 'extracoding CEBPA' (ecCEBPA) because it encompasses the entire mRNA sequence in the same-sense orientation. ecCEBPA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extended the generality of this finding to numerous gene loci. Di Ruscio et al. (2013) concluded that these results delineated the nature of DNMT1-RNA interactions and suggested strategies for gene-selective demethylation of therapeutic targets in human diseases.
Nishiyama et al. (2013) showed that UHRF1 (607990)-dependent histone H3 ubiquitylation has a prerequisite role in the maintenance of DNA methylation. Using Xenopus egg extracts, Nishiyama et al. (2013) successfully reproduced maintenance DNA methylation in vitro. DNMT1 depletion resulted in a marked accumulation of UHRF1-dependent ubiquitylation of histone H3 at lysine-23. DNMT1 preferentially associates with ubiquitylated H3 in vitro through a region previously identified as a replication foci targeting sequence. The RING finger mutant of UHRF1 failed to recruit DNMT1 to DNA replication sites and to maintain DNA methylation in mammalian cultured cells. Nishiyama et al. (2013) concluded that their findings represented the first evidence of the mechanistic link between DNA methylation and DNA replication through histone H3 ubiquitylation.
Li et al. (2018) demonstrated that loss of Stella (DPPA3; 608408) in mouse oocytes led to ectopic nuclear accumulation of the DNA methylation regulator UHRF1, which resulted in the mislocalization of maintenance DNA methyltransferase DNMT1 in the nucleus. Genetic analysis confirmed the primary role of UHRF1 and DNMT1 in generating the aberrant DNA methylome in Stella-deficient oocytes. Li et al. (2018) concluded that Stella therefore safeguards the unique oocyte epigenome by preventing aberrant de novo DNA methylation mediated by DNMT1 and UHRF1.
By pentuple knockout (PKO) of Tet1 (607790), Tet2 (612839), and Tet3 (613555), which are involved in demethylation, and the de novo DNA methyltransferases Dnmt3a and Dnmt3b, Wang et al. (2020) found that DNA methylation was dispensable for self-renewal and pluripotency in mouse embryonic stem cells (mESCs). Further analysis showed that the methylome in PKO mESCs was maintained by Dnmt1, with residual de novo methyltransferase activity by Dnmt3c (see 602900). PKO mESCs were able to propagate the DNA methylome during differentiation toward neurons, but they showed severe differentiation defects, as they lost regulatory plasticity of methylation at individual loci. Furthermore, a clonal population of Dnmt1-only cells (PKO cells that also lacked Dnmt3c) produced a heterogeneous methylome, or spontaneous epimutations, during clonal expansion due to imprecise maintenance activity and de novo activity of Dnmt1. Spontaneous epimutations were corrected over time toward an expected state consistent with neighborhood DNA methylation density, a process the authors termed neighbor-guided correction. Wang et al. (2020) noted that the same factors that generate spontaneous epimutations also played critical roles in maintenance of a robust methylome through this neighbor-guided correction mechanism.
Reviews
Bestor (2000) presented a review of the mammalian DNA methyltransferases, including the structure and function of Dnmt1 and its sex-specific promoters and exons.
Baylin (1997) gave a general review of DNA methylation in relation to imprinting and cancer. DNA methylation is absent in Drosophila, C. elegans, and yeast, but appears as the vertebrate genome becomes more complex. Concurrently, during evolution, the CpG dinucleotide, the principal site of DNA methylation, became selectively depleted through conversion of methylated cytosines to thymidines via a deamination process. The human genome has only 10% of the expected frequency of CpGs, and 70 to 80% of these are methylated. However, small regions of DNA (1 to 2%) remain that are not CpG-depleted and are termed CpG islands. These are rigorously protected from methylation and are associated with the transcription start sites in almost half, or some 40,000, human genes. DNA methylation patterns correlate closely with patterns of gene expression. Heavily methylated DNA is generally associated with chromatin organization that is inhibitory to transcription. In contrast, the unmethylated CpG islands of most genes are associated with chromatin typical of highly transcribed DNA. Selected CpG islands are densely methylated. These regions have chromatin conformation typical of nontranscribed DNA and represent silenced alleles for monoallelically expressed or 'imprinted' genes and for most genes on the transcriptionally inactivated X chromosome of the female. With homozygous deletion of the MCMT gene in mouse and embryos, death occurs early in embryogenesis. Cancer cells show altered patterns of DNA methylation. Overall DNA methylation is often decreased; this change may contribute to genomic instability. In these same tumors, the normally unmethylated CpG islands in the promoter region of critical genes can become densely methylated, and the associated transcriptional silencing is an epigenetic alternative to coding region mutations for causing loss of tumor suppressor gene function. As reviewed by Baylin (1997), almost half of the suppressor genes known to underlie genetic forms of neoplasia, including VHL (608537) and p16 (CDKN2A; 600160), when mutated in the germline exhibit CpG island hypermethylation in noninherited cancers.
Hereditary Sensory Neuropathy Type IE
By linkage analysis followed by exome sequencing, Klein et al. (2011) identified 2 different heterozygous mutations in the DNMT1 gene (126375.0001 and 126375.0002) in 4 unrelated families with autosomal dominant inheritance of hereditary sensory neuropathy type IE (HSN1E; 614116). In vitro functional expression studies in E. coli and HeLa cells showed that the mutations affected proper folding of DNMT1 and resulted in premature degradation, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site-specific hypermethylation. These changes indicated epigenetic dysregulation. The results provided a direct link between DNMT1 defects and a neurodegenerative disorder affecting both the central and peripheral nervous systems, and suggested that DNMT1 participates in a precise mechanism of dynamic regulation of neuronal survival.
Klein et al. (2013) identified 2 different heterozygous mutations affecting the same codon in exon 20 of the DNMT1 gene (Y495C, 126375.0001 and Y495H, 126375.0006) in affected members of 2 unrelated families with HSN1E. DNMT1 mutations were specific to the phenotype of peripheral neuropathy associated with hearing loss and dementia, as mutations were not found in 48 patients with sensory neuropathy without hearing loss or dementia or in 5 kindreds with familial frontotemporal dementia. Mutations in exons 20 and 21 of the DNMT1 gene were also not found in 364 patients with late-onset Alzheimer disease, thus likely excluding a role for this gene in AD linked to chromosome 19p13.2 (AD9; 608907).
Cerebellar Ataxia, Deafness, and Narcolepsy
In affected members of 4 families with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCADN; 604121), Winkelmann et al. (2012) identified 3 different heterozygous mutations in exon 21 of the DNMT1 gene (126375.0003-126375.0005). The first mutations were identified by exome sequencing. The disorder was characterized by adult onset of progressive cerebellar ataxia, narcolepsy/cataplexy, sensorineural deafness, and dementia. More variable features included optic atrophy, sensory neuropathy, psychosis, and depression. Winkelmann et al. (2012) postulated that the DNMT1 mutations may result in aberrant gene expression or silencing in particular neuronal cells. The authors also noted that DNMT1 is expressed in immune cells, which may play a role in narcolepsy.
DNMT1 Variant Function in HSN1E and ADCADN Patients
Maresca et al. (2020) evaluated the effects of DNMT1 mutations in fibroblasts from 6 previously reported patients, 4 with ADCADN (A570V, 126375.0004; E575K; G605A, 126375.0005; V606F, 126375.0003) and 2 with HSN1E (P507R and K521del). All 6 mutations were predicted to affect the 3D structure of the protein. Expression studies of the mutants in E. coli showed that DNMT1 enzyme activity was reduced in the mutant proteins from patients with ADCADN compared to wildtype, and that enzyme activity was less efficient in the mutant proteins from patients with HSN1E, resulting in undetectable protein. Mitochondrial functional studies in patient fibroblasts showed that all of the mutants except E575K and K521del had significantly increased oxidative metabolism, and cellular ATP levels were generally reduced, likely due to increased ATP-consuming pathways. Metabolomic profiling in the fibroblasts showed alterations in purine, glutamate, and arginine/urea cycle pathways.
Li et al. (1992) used gene targeting in embryonic stem (ES) cells to mutate the murine DNA methyltransferase gene. ES cell lines homozygous for the mutation were generated by consecutive targeting of both wildtype alleles; the mutant cells were viable and showed no obvious abnormalities with respect to growth rate or morphology, and had only trace levels of DNA methyltransferase activity. When introduced into the germline of mice, the mutation was found to cause a recessive lethal phenotype. Homozygous embryos were stunted, delayed in development, and did not survive past midgestation. The DNA of homozygous embryos showed a reduction in the level of 5-methylcytosine similar to that of homozygous ES cells.
The absence of endogenous methylation in Drosophila facilitates detection of experimentally induced methylation changes. Lyko et al. (1999) expressed Dnmt1 and Dnmt3a in transgenic Drosophila melanogaster. In this system, Dnmt3a functioned as a de novo methyltransferase, whereas Dnmt1 had no detectable de novo methylation activity. When coexpressed, Dnmt1 and Dnmt3a cooperated to establish and maintain methylation patterns. Genomic DNA methylation impaired the viability of transgenic flies, suggesting that cytosine methylation has functional consequences for Drosophila development. The expression of Dnmt3a but not Dnmt1 caused developmental defects in Drosophila, with the majority dying in the pupal stage. Tissue-specific expression of Dnmt3a in the Drosophila eye resulted in small or absent eyes.
Maintenance of genomic methylation patterns in mammalian somatic cells depends on Dnmt1. Mouse oocytes and preimplantation embryos lack Dnmt1 but express a variant called Dnmt1o. Howell et al. (2001) eliminated Dnmt1o by deletion of the oocyte-specific promoter and first exon from the Dnmt1 locus. Homozygous animals were normal, but most heterozygous fetuses of homozygous females died during the last third of gestation. Although genomic methylation patterns were established normally in Dnmt1o-deficient oocytes, embryos derived from such oocytes showed a loss of allele-specific expression and methylation at certain imprinted loci. Transient nuclear localization of Dnmt1o in 8-cell embryos suggested that this variant of Dnmt1 provides maintenance methyltransferase activity specifically at imprinted loci during the fourth embryonic S phase.
Using Cre/loxP-mediated deletion of Dnmt1 in mice at sequential stages of T-cell development, Lee et al. (2001) showed that inactivation in early double-negative thymocytes led to impaired survival of T-cell receptor (TCR) alpha (see 186880)/beta (see 186930)-positive cells and the generation of atypical CD8 (see 186910)-positive TCR gamma (see 186970)/delta (see 186810)-positive cells. In the double-positive thymocyte stage, deletion instead impaired activation-induced proliferation and caused differential enhancement of cytokine mRNA expression in naive peripheral T cells. Lee et al. (2001) attributed the increased cytokine expression primarily to demethylation in cis of certain cytokine genes.
To study the interaction between DNA mismatch repair and DNA methylation, Trinh et al. (2002) introduced a Dnmt1 mutation into a mouse strain deficient for a mismatch repair protein, Mlh1 (120436). Mice harboring the hypomorphic Dnmt1 mutation alone showed diminished Dnmt1 RNA expression and DNA hypomethylation, but they developed normally. When crossed with homozygous Mlh1 null mice, they were less likely to develop the intestinal cancers that normally arise in the mismatch repair-deficient background. However, these same mice developed invasive T- and B-cell lymphomas earlier and at a much higher frequency than their Dnmt1 wildtype littermates.
Using wildtype and mutant mouse embryonic stem cells, Biniszkiewicz et al. (2002) studied the intrinsic susceptibility of several imprinted genes to Dnmt1 overexpression. The nonmethylated imprinted region of Igf2 (147470) and H19 (103280) were resistant to methylation at low Dnmt1 levels, but became fully methylated when Dnmt1 was overexpressed from a BAC transgene. Methylation caused the activation of the silent Igf2 allele in wildtype and Dnmt1 knockout cells, leading to biallelic Igf2 expression. In contrast, several other imprinted genes were completely resistant to de novo methylation when Dnmt1 was overexpressed. Injection of Dnmt1-overexpressing embryonic stem cells in diploid or tetraploid mouse blastocysts resulted in lethality of the embryo, which resembled the embryonic lethality caused by Dnmt1 deficiency.
Gaudet et al. (2003) generated mice carrying a hypomorphic Dnmt1 allele, which reduced Dnmt1 expression to 10% of wildtype levels and resulted in substantial genomewide hypomethylation in all tissues. The mutant mice, who carried the hypomorphic mutation on 1 allele and full knockout on the other, were runted at birth, and at 4 to 8 months of age developed aggressive T cell lymphomas that displayed a high frequency of chromosome 15 trisomy. Gaudet et al. (2003) concluded that DNA hypomethylation plays a causal role in tumor formation, possibly by promoting chromosomal instability. However, Yang et al. (2003) argued that Gaudet et al. (2003) used extreme modeling in their mice and drew excessively negative conclusions regarding the implications of hypomethylating agents for the treatment of cancer in patients. Yang et al. (2003) found relatively little hypomethylation in colon cancer cells from 19 colon cancers relative to normal colonic mucosa and found no long-term nor short-term ill effects from treatment with 5-aza-2-prime-deoxycytidine (5-aza-cD) in 53 patients with leukemia who survived 6 months or longer after initiation of therapy. Eden et al. (2003) countered that side effects in short-term treatment of cancer patients may be of little relevance, but that long-term prophylactic treatment aimed at protecting against cancer incidence in one tissue may have the unwanted side effect of promoting tumors in other tissues.
Miller and Sweatt (2007) found that DNA methylation mediated by DNMTs was dynamically regulated during learning and memory consolidation in adult rats. Animals exposed to an associative context plus shock showed increased Dnmt3a and Dnmt3b mRNA in hippocampal area CA1 compared to context-only animals. Context plus shock rats showed increased methylation and decreased mRNA of the memory suppressor gene PP1C-beta (PPP1CB; 600590) compared to shock-only controls, as well as increased demethylation and increased mRNA levels of reelin (RELN; 600514), a gene involved in synaptic plasticity, compared to controls. The methylation levels of both these target genes returned to baseline within a day, indicating rapid and dynamic changes. Treatment with a DNMT inhibitor blocked the methylation changes and prevented memory consolidation of fear-conditioned learning, but the memory changes were plastic, and memory consolidation was reestablished after the inhibitor wore off. Miller and Sweatt (2007) noted that DNA methylation has been viewed as having an exclusive role in development, but they emphasized that their findings indicated that rapid and dynamic alteration of DNA methylation can occur in the adult central nervous system in response to environmental stimuli during associative learning in the hippocampus.
Hutnick et al. (2009) generated conditional Dnmt1-mutant mice that possessed approximately 90% hypomethylated cortical and hippocampal cells in the dorsal forebrain from embryonic day (E) 13.5 through adulthood. The Dnmt1-mutant mice were viable with a normal life span, but displayed severe neuronal cell death between E14.5 and 3 weeks postnatally. In addition to cortical and hippocampal degeneration, adult Dnmt1-mutant mice exhibited neurobehavioral defects in learning and memory. Unexpectedly, a fraction of Dnmt1 -/- cortical neurons survived throughout postnatal development, so that the residual cortex in mutant mice contained 20 to 30% of hypomethylated neurons across the life span. Hypomethylated excitatory neurons exhibited multiple defects in postnatal maturation including abnormal dendritic arborization and impaired neuronal excitability. The mutant phenotypes were coupled with deregulation of those genes involved in neuronal layer specification, cell death, and the function of ion channels. Hutnick et al. (2009) suggested that DNA methylation, through its role in modulating neuronal gene expression, may play multiple roles in regulating cell survival and neuronal maturation in the central nervous system.
Beck et al. (2021) found that mice with epidermis-specific Dnmt1 deletion were born at normal mendelian ratios and initially displayed normal epidermal development, with regular barrier formation and unaffected differentiation. However, mutant mice developed a skin pathology at postnatal day-3 (P3), began losing weight at P6, and died between P8 and P9. Mutant mice exhibited a 60% reduction in genomewide DNA methylation in epidermal cells, leading to an elevated innate immune response in epidermis, disruption of epidermal homeostasis, and severe skin pathology. Induction of the innate immune system in mutant epidermis was not dependent on Mda5 (IFIH1; 606951)/Mavs (609676) signaling. Instead, loss of Dnmt1 in keratinocytes induced chromosomal instability and disrupted cell cycle progression, resulting in formation of DNA blebs and DNA micronuclei in cytoplasm. These cytoplasmic DNAs were detected by cGas (613973), which induced a strong innate immune response in mutant mice. Deletion of cGAS ameliorated the autoimmune phenotype of mutant mice, indicating that activation of the innate immune system via the cGas/Sting (STING1; 612374) pathway was a critical component of the inflammatory skin disease observed in mutant mice.
Kawasaki and Taira (2004) reported that disruption of the expression of DNMT1 or DNMT3B (602900) by specific short interfering RNAs (siRNAs) abolished the siRNA-mediated methylation of DNA, but the report was retracted.
In affected members of 2 large American kindreds and 1 Japanese kindred with autosomal dominant inheritance of hereditary sensory neuropathy type IE (HSN1E; 614116) with sensorineural hearing loss and early-onset dementia, Klein et al. (2011) identified a heterozygous 1484A-G transition in exon 20 of the DNMT1 gene, resulting in a tyr495-to-cys (Y495C) substitution. The mutation occurred in the targeting-sequence domain of the protein, in the N-terminal regulatory region required for enzymatic function. The mutation was not found in over 1,500 controls. Two of the kindreds had previously been reported by Wright and Dyck (1995) and Hojo et al. (1999), respectively. In vitro functional expression studies in E. coli and HeLa cells showed that the mutation affected proper folding of DNMT1 and resulted in premature protein degradation, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site-specific hypermethylation. These changes indicated epigenetic dysregulation.
Klein et al. (2013) identified a heterozygous Y495C mutation in affected members of a family from Scotland with HSN1E. A family of Norwegian origin with the same phenotype was found to carry a different mutation affecting the same codon (Y495H; 126375.0006), suggesting a mutation hotspot.
In affected members of a European family with autosomal dominant hereditary sensory neuropathy type IE (HSN1E; 614116) with sensorineural hearing loss and early-onset dementia, Klein et al. (2011) identified a heterozygous change in 3 consecutive nucleotides in exon 20 of the DNMT1 gene: 1470_1472TCC-ATA, resulting in an asp490-to-glu (D490E) and pro491-to-tyr (P491Y) substitution on 1 allele. The substitutions occurred in the targeting-sequence domain in the N-terminal regulatory region required for enzymatic function. The mutations were not found in over 1,500 controls. In vitro functional expression studies in E. coli and HeLa cells showed that the mutations affected proper folding of DNMT1 and resulted in premature degradation, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site-specific hypermethylation. These changes indicated epigenetic dysregulation.
In affected members of a Swedish family with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCADN; 604121), originally reported by Melberg et al. (1995), Winkelmann et al. (2012) identified a heterozygous c.1816C-A transversion in exon 21 of the DNMT1 gene, resulting in a val606-to-phe (V606F) substitution at a highly conserved residue in the replication foci targeting sequence (RFTS) domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in 507 control exomes or in the 1000 Genomes Project database. Functional studies were not performed, but the location of the mutation suggested that it may affect DNA binding recognition or interaction with other proteins.
In affected members of an American family with cerebellar ataxia, deafness, and narcolepsy (ADCADN; 604121), Winkelmann et al. (2012) identified a heterozygous c.1709G-A transition in exon 21 of the DNMT1 gene, resulting in an ala570-to-val (A570V) substitution at a highly conserved residue in the RFTS domain. An unrelated Italian patient with the disorder also carried a heterozygous de novo A570V substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in 507 control exomes or in the 1000 Genomes Project database. Functional studies of the mutation were not performed, but the location of the mutation suggested that it may affect DNA binding recognition or interaction with other proteins.
In affected members of an Italian family with cerebellar ataxia, deafness, and narcolepsy (ADCADN; 604121), Winkelmann et al. (2012) identified a heterozygous c.1814C-G transversion in exon 21 of the DNMT1 gene, resulting in a gly605-to-ala (G605A) substitution at a highly conserved residue in the RFTS domain. Functional studies were not performed, but the location of the mutation suggested that it may affect DNA binding recognition or interaction with other proteins.
In affected members of a family of Norwegian descent with hereditary sensory neuropathy type IE (HSN1E; 614116), Klein et al. (2013) identified a heterozygous c.1483T-C transition in exon 20 of the DNMT1 gene, resulting in a tyr495-to-his (Y495H) substitution in the targeting sequence domain. A different mutation at the same codon (Y495C; 126375.0001) has been identified in several other families with a similar phenotype, suggesting a mutation hotspot.
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