Table 1.
DNA methyltransferase deletion studies
| Model | Phenotype | Reference |
|---|---|---|
| Global DNMT1 null mice | 3-fold reduction in genomic 5mC levels | [13] |
| Recessive embryonic lethal | ||
| Embryos are developmentally retarded | ||
| Embryos die at mid-gestation | ||
| DNMT3A-/- | DNMT3A-/- mice appear normal at birth but become runted and die at around 4 weeks of age | [6] |
| DNMT3B-/- mice | DNMT3B-/- mice exhibit growth impairment, rostral neural tube defects and die at mid-gestation | |
| DNMT1o knockout mice | Heterozygous embryos from homozygous mutant females die during last third of gestation | [178] |
| Loss of methylation at imprinted loci | ||
| DNMT3L knockout mice | Azoospermia in homozygous males | [33] |
| Heterozygous embryos from homozygous mutant females die during mid-gestation | ||
| Loss of maternal methylation imprints | ||
| Cre-mediated homozygous DNMT1 deletion in fibroblasts | DNMT1 deletion leads to hypomethylation and aberrant expression of 10% of genes | [15] |
| DNMT1 depleted cells undergo p53-mediated apoptosis | ||
| Cre-mediated DNMT1 deletion in neuroblasts | 95% of cells in the brain hypomethylated | [179] |
| (CamK-cre) | Die immediately after birth from respiratory distress; defects in neuronal respiratory control | |
| Cre-mediated DNMT1 deletion in telencephalic precursors | Mutant mice viable but undergo severe neuronal cell death from E14.5-P21 | [180] |
| (Emx1-cre) | Deregulation of neuronal gene expression | |
| Defects in neuronal morphology and excitability | ||
| shRNA knockdown of DNMT1 in primary human keratinocytes | DNMT1 depleted cells exit progenitor compartment, undergo premature differentiation | [92] |
| DNMT1 loss results in upregulation of cyclin-dependent kinase inhibitors, cell cycle arrest and impaired proliferation | ||
| Cre-mediated DNMT1 deletion in hematopoietic stem cells (HSC) | Impaired HSC self-renewal | [181] |
| (Mx-cre) | Increased cell cycling and inappropriate expression of differentiation markers in myeloid progenitor cells | |
| Cre-mediated DNMT1 deletion in pancreatic cells | DNMT1 loss results in de-repression of p53 | [79] |
| (Pdx1-cre) | G2/M cell cycle arrest and apoptosis | |
| Pancreatic agenesis due to apoptosis of progenitors | ||
| Cre-mediated DNMT1 deletion in retinal cells | Defective photoreceptor differentiation | [182] |
| (Chx10-cre) | Altered cell cycle kinetics; increased proportion of G1 phase cells | |
| Increased apoptosis of post-mitotic photoreceptors and other neuronal types | ||
| Cre-mediated DNMT1 deletion in retinal cells | Mice have smaller eyes | [183] |
| (Rx-cre) | Impaired differentiation of retinal pigment epithelium | |
| Defects in photoreceptor outer segment morphogenesis | ||
| Cre-mediated DNMT1 deletion in intestinal cells | Mice die few weeks after birth | [80] |
| (Villin-cre) | Induction of differentiation markers in progenitor cells | |
| Impaired methylation and expression of DNA damage response genes and cell cycle regulators | ||
| Increased DNA damage and apoptosis of progenitor cells | ||
| Cre-mediated DNMT1 deletion in Keratin 14 lineage cells | Uneven epidermal thickness, altered hair follicle size | [184] |
| (K14-cre) | Impaired proliferation at hair follicles, progressive alopecia with age | |
| Cre-mediated DNMT1 deletion in Shh lineage cells | Mice die shortly after birth; respiratory complications arising from severe lung hypoplasia | [81,82] |
| (Shh-cre) | Epithelial depletion of urethral and bladder epithelium | |
| Premature differentiation and loss of bladder progenitors | ||
| Cell cycle arrest and apoptosis of prostate progenitors; reduction in prostate bud number |