Paternal Imprinting Research Articles

Parent of origin genetic effects on milk production traits in a population of Iranian Holstein cows.

The aim was to estimate the relative contribution of imprinting effects from both paternal and maternal sides to phenotypic variation in milk production traits including 305 days milk yield (MY), average daily milk production (ADM), fat percentage (F%), protein percentage (P%), 305 days fat yield (FY), 305 days protein yield (PY), ratio of fat percentage to protein percentage (F:P) and somatic cell score (SCS) in Iranian Holstein cows. To do this, each trait was analysed with a series of four animal models, which were identical for fixed and additive genetic effects but differed for combinations of paternal and maternal imprinting effects. The log-likelihood ratio test (LRT) and Akaike's information criteria (AIC) were used to select the best model for each trait. Correlations between traits due to additive and imprinting effects were estimated by bivariate analyses. For all traits studied, fitting the imprinting effect led to a better data fit. Also, it resulted in a noticeable decrease in additive genetic variance from 8% (SCS) to 28% (F:P). A significant maternal imprinting effect was detected on all traits studied. Estimates of maternal imprinting heritability ( ) were 0.07 ± 0.02, 0.04 ± 0.01, 0.06 ± 0.01, 0.05 ± 0.01, 0.5 ± 0.01, 0.09 ± 0.02, 0.07 ± 0.02 and 0.06 ± 0.01 for MY, ADM, F%, P%, FY, PY, F:P and SCS, respectively. For F:P, in addition to the maternal imprinting effect, a significant paternal imprinting component was also detected with a 7% contribution to phenotypic variance of F:P. Estimates of direct heritability ( ) were 0.29 ± 0.02, 0.17 ± 0.01, 0.22 ± 0.02, 0.11 ± 0.01, 0.18 ± 0.02, 0.22 ± 0.02, 0.15 ± 0.04 and 0.06 ± 0.01 for MY, ADM, F%, P%, FY, PY, F:P and SCS, respectively. Maternal imprinting correlations (rmi) were in a wide range between -0.75 ± 0.15 (P%-SCS) and 0.95 ± 0.11 (MY-ADM). Additive genetic correlations (ra) ranged between -0.54 ± 0.05 (MY-P%) and 0.99 ± 0.01 (MY-ADM) and phenotypic correlations (rp) ranged from -0.30 ± 0.01 (MY-F%) to 0.93 ± 0.01 (MY-ADM). The Spearman's correlation between additive breeding values including and excluding imprinting effects deviated from unity especially for top-ranked animals implying re-ranking of top animals following the inclusion of imprinting effects in the model. Since including imprinting effects in the model resulted in better data fit and re-ranking of top animals, including these effects in the genetic evaluation models for milk production traits was recommended.

The Effects of Paternal Nurturant Imprint (PNI) on Work-Family Functioning

The Effects of Paternal Nurturant Imprint (PNI) on Work-Family Functioning

Role of transcription in imprint establishment in the male and female germ lines.

The authors highlight an area of research that focuses on the establishment of genomic imprints: how the female and male germlines set up opposite instructions for imprinted genes in the maternally and paternally inherited chromosomes. Mouse genetics studies have solidified the role of transcription across the germline differentially methylated regions in the establishment of maternal genomic imprinting. One work now reveals that such transcription is also important in paternal imprinting establishment. This allows the authors to propose a unifying mechanism, in the form of transcription across germline differentially methylated regions, that specifies DNA methylation imprint establishment. Differences in the timing, genomic location and nature of such transcription events in the male versus female germlines in turn explain the difference between paternal and maternal imprints.

Establishment of paternal methylation imprint at the H19/Igf2 imprinting control region.

The insulator model explains the workings of the H19 and Igf2 imprinted domain in the soma, where insulation of the Igf2 promoter from its enhancers occurs by CTCF in the maternally inherited unmethylated chromosome but not the paternally inherited methylated allele. The molecular mechanism that targets paternal methylation imprint establishment to the imprinting control region (ICR) in the male germline is unknown. We tested the function of prospermatogonia-specific broad low-level transcription in this process using mouse genetics. Paternal imprint establishment was abnormal when transcription was stopped at the entry point to the ICR. The germline epimutation persisted into the paternal allele of the soma, resulting in reduced Igf2 in fetal organs and reduced fetal growth, consistent with the insulator model and insulin-like growth factor 2 (IGF2)'s role as fetal growth factor. These results collectively support the role of broad low-level transcription through the H19/Igf2 ICR in the establishment of its paternal methylation imprint in the male germ line, with implications for Silver-Russell syndrome.

Susceptibility to azoospermia by haplotype analysis of protamine 1 and protamine 2 variants

Infertility remains a major global problem, affecting 10–15% of couples worldwide, with half of the cases due to male factors. Protamines, found only in the testes, are essential for sperm chromatin condensation and paternal genome imprinting during spermatogenesis. Seventy testicular samples from infertile men were analyzed for the expression level of PRM1 and PRM2. 448 infertile males were additionally examined for PRM1 and PRM2 polymorphism. There was a significant association of rs2070923 polymorphism of PRM2 in both additive and recessive models (OR (95% CI) 1.32[0.92; 1.88, p = 0.023] and 2.26[1.12; 4.57, p = 0.017], respectively). The TT genotype of rs2070923 PRM2 was also correlated with lower gene expression of PRM2 in the infertile group (p = 0.03). Moreover, our result showed that the frequency of GTCT haplotype was higher than average in azoospermic patients (OR = 2.67; 95%CI = 1.17–2.53; p = 0.041) and that gene-gene interaction played a role in male infertility. The linkage disequilibrium plot showed that rs2301365 was strongly associated with rs2070923. For the first time, we reported a significant haplotype of PRM1 and PRM2 genes associated with male infertility in Iranian population. These results are likely to contribute to a better understanding of the causes of male infertility.

Transgenerational Paternal Inheritance of TaCKX GFMs Expression Patterns Indicate a Way to Select Wheat Lines with Better Parameters for Yield-Related Traits.

Members of the TaCKX gene family (GFMs) encode the cytokinin oxygenase/dehydrogenase enzyme (CKX), which irreversibly degrades cytokinins in the organs of wheat plants; therefore, these genes perform a key role in the regulation of yield-related traits. The purpose of the investigation was to determine how expression patterns of these genes, together with the transcription factor-encoding gene TaNAC2-5A, and yield-related traits are inherited to apply this knowledge to speed up breeding processes. The traits were tested in 7 days after pollination (DAP) spikes and seedling roots of maternal and paternal parents and their F2 progeny. The expression levels of most of them and the yield were inherited in F2 from the paternal parent. Some pairs or groups of genes cooperated, and some showed opposite functions. Models of up- or down-regulation of TaCKX GFMs and TaNAC2-5A in low-yielding maternal plants crossed with higher-yielding paternal plants and their high-yielding F2 progeny reproduced gene expression and yield of the paternal parent. The correlation coefficients between TaCKX GFMs, TaNAC2-5A, and yield-related traits in high-yielding F2 progeny indicated which of these genes were specifically correlated with individual yield-related traits. The most common was expressed in 7 DAP spikes TaCKX2.1, which positively correlated with grain number, grain yield, spike number, and spike length, and seedling root mass. The expression levels of TaCKX1 or TaNAC2-5A in the seedling roots were negatively correlated with these traits. In contrast, the thousand grain weight (TGW) was negatively regulated by TaCKX2.2.2, TaCKX2.1, and TaCKX10 in 7 DAP spikes but positively correlated with TaCKX10 and TaNAC2-5A in seedling roots. Transmission of TaCKX GFMs and TaNAC2-5A expression patterns and yield-related traits from parents to the F2 generation indicate their paternal imprinting. These newly shown data of nonmendelian epigenetic inheritance shed new light on crossing strategies to obtain a high-yielding F2 generation.

Expression patterns and DNA methylation profile of GTL2 gene in goats

Gene trap locus 2 (GTL2), a long non-coding paternal imprinting gene, participates in various biological processes, including cell proliferation, differentiation, and apoptosis, by regulating the transcription of target mRNA, which is tightly related to the growth of the organic and maintenance of function. In this study, DNA methylation patterns of CpG islands (CGI) of GTL2 were explored, and its expression level was quantified in six tissues, rumen epithelium cells, and skeletal muscle cells in goats. GTL2 expression levels were measured by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and the methylation model was confirmed by bisulfite-sequencing PCR (BSP). CGI methylation of GTL2 indicated a moderate methylation (ranging from 81.42 to 86.83%) in the brain, heart, liver, kidney, lung, and longissimus dorsi. GTL2 is most highly expressed in brain tissues, but there is no significant difference in the other five tissues. In addition, in the rumen epithelium cell proliferation, GTL2 expression was highest at 60 h, followed by 72 h, and almost unchanged at 12–48 h. In the skeletal muscle cell differentiation, GTL2 expression was highest at 0 and 24 h, significantly decreasing at 72 and 128 h. Pearson correlation analysis did not indicate a clear relationship between methylation and GTL2 expression levels, suggesting that other regulatory factors may modulate GTL2 expression. This study will provide a better understanding of the expression regulation mechanism of genes in the delta-like homolog 1 gene (DLK1)-GTL2 domain.

Generation of blastoids from human parthenogenetic stem cells

Abstract Parthenogenetic embryos derive their genomes entirely from the maternal genome and lack paternal imprint patterns. Many achievements have been made in the study of genomic imprinting using human parthenogenetic embryonic stem cells (hPg-ESCs). However, due to developmental defects and ethical limits, a comprehensive understanding of parthenogenetic embryonic development is still lacking. Here, we generated parthenogenetic blastoids (hPg-EPSCs blastoids) from hPg-ESC-derived extended pluripotent stem cells (hPg-EPSCs) using our previously published two-step induction protocol. Morphology, specific marker expression and single-cell transcriptome analysis showed that hPg-EPSCs blastoids contain crucial cell lineages similar to blastoids (hBp-EPSCs blastoids) generated from human biparental EPSCs (hBp-EPSCs). Single-cell RNA-seq compared the expression of genes related to imprinting and X chromosome inactivation in hPg-EPSCs blastoids and hBp-EPSCs blastoids. In conclusion, we generated parthenogenetic blastoids, which will potentially promote the study of genomic imprinting in embryonic development and uncover the influence of parental origin bias on human development and pathological mechanisms.

Genetic analysis of parent-of-origin effects on growth traits and yearling greasy fleece weight in Raeini Cashmere goat

Pedigree on 7253 individuals and data information on growth traits and greasy yearling fleece weight collected from 1979 to 2013 at the Breeding Station of Raeini Cashmere goat, south-east of Iran, were used for genetic analysis of parent of origin effects for these traits using a gametic relationship matrix. The studied traits included birth weight (BW; 4747 records), weaning weight (WW; 3268 records), six months weight (6 MW; 2855 records), nine months weight (9 MW; 1407 records), yearling weight (YW; 1013 records), and yearling greasy fleece weight (YFW; 1272 records). Models including or excluding imprinting (maternal and paternal) effects were compared by applying Akaike Information Criterion (AIC). Paternal imprinting effects did not influence any of the studied traits. Maternal imprinting effects explained 9%, 6%, 9%, 18%, and 6% of phenotypic variances for WW, 6 MW, 9 MW, YW, and YFW, respectively. By including the maternal imprinting effects in the model used for genetic analysis, direct heritability estimates for WW (from 0.04 to 0.01), 9 MW (0.24–0.15), YW (from 0.31 to 0.14), and YFW (0.18–0.09) were decreased, implying a considerable proportion of the maternal imprinting effects for these traits may overlap with direct additive genetic effects. BW did not influence by imprinting effects. Strong maternal imprinting correlations among body weights at different ages (except for BW) showed that WW, 6 MW, 9 MW, and YW share similar genes with maternally imprinted effects. It means that the imprinting effects of genes are not limited to a specific stage of life and can be active in different stages of growth. Maternal imprinting correlation estimates between YFW and other traits were not statistically significant. Therefore, imprinting effects may be crucial for the genetically evaluating of these traits in the Raeini Cashmere goat.

Paternal imprinting of dosage-effect defective1 contributes to seed weight xenia in maize

Historically, xenia effects were hypothesized to be unique genetic contributions of pollen to seed phenotype, but most examples represent standard complementation of Mendelian traits. We identified the imprinted dosage-effect defective1 (ded1) locus in maize (Zea mays) as a paternal regulator of seed size and development. Hypomorphic alleles show a 5–10% seed weight reduction when ded1 is transmitted through the male, while homozygous mutants are defective with a 70–90% seed weight reduction. Ded1 encodes an R2R3-MYB transcription factor expressed specifically during early endosperm development with paternal allele bias. DED1 directly activates early endosperm genes and endosperm adjacent to scutellum cell layer genes, while directly repressing late grain-fill genes. These results demonstrate xenia as originally defined: Imprinting of Ded1 causes the paternal allele to set the pace of endosperm development thereby influencing grain set and size.

Relative contribution of Imprinting, X chromosome and Litter effects to phenotypic variation in economic traits of sheep.

Data on Zandi sheep were analysed to quantify maternal and paternal imprinting, X chromosome and litter effects' contribution to phenotypic variation in birth weight (BW), weaning weight (WW), growth rate (GR), Kleiber ratio (KR), efficiency of growth (EF) and relative growth rate (RGR). To this end, a two-step approach was adopted. In the first step, each trait was analysed with a series of 16 animal models, which were identical for fixed and autosomal additive genetic effects but differed for combinations of maternal permanent environmental, maternal genetic, X chromosome and litter effects. For each trait, the best model was selected by the Akaike information criterion (AIC) and likelihood ratio tests (LRTs). In the second step, three additional models were fitted by adding maternal imprinting, paternal imprinting or both (models 17, 18 and 19) to the best model selected in the first step. Estimators of bias, dispersion and accuracy of breeding values estimated within 19 models with whole, and partial data were used to evaluate how well were the 19 models in estimating breeding values for the animals when their records were masked. For all traits studied, fitting the litter effect led to a better data fit. Also, it resulted in noticeable decreases in residual variance and other maternal variances. For growth traits, models containing the X-linked effects fitted the data substantially better than corresponding models without the X-linked effects. For BW, WW and GR, estimates of X-linked heritability ( ) ranged between 0.09 (GR) and 0.14 (BW). Ignoring X-linked effects from the genetic evaluation model resulted in significant inflated autosomal additive genetic variance. For BW, WW, EF and RGR, models containing the imprinting effects provided a better fit of the data than otherwise identical models. Imprinting effects contributed significantly to the phenotypic variation of these traits in a range between 5% (RGR) and 8% (BW, WW). A sharp decline was observed in autosomal additive genetic variance following including imprinting effects in the model (27% to 40% depending on the trait). The least bias and dispersion, as well as greater accuracies for breeding values of focal animals, were for a model which included imprinting, X-linked and litter effects. It was concluded that imprinting, X-linked and litter effects need to be included in the genetic evaluation models for growth and efficiency-related traits of Zandi lambs.

Parental imprinting effects on growth traits and Kleiber ratio in sheep

AbstractThe goal was to study imprinting effects on birth weight (BW), weaning weight (WW), six months weight (W6), pre- and post-weaning growth rate (GRa and GRb), and pre- and post-weaning Kleiber ratio (KRa and KRb) in Baluchi and Makuie sheep breeds. Analyses were done in a two steps process. In the first step, each trait was analysed with a series of 12 univariate animal models, including different combinations of direct and maternal effects and the best model was selected by the AIC criterion. In the second step, three new models were fitted by adding either maternal imprinting effect, paternal imprinting effect, or both of them, respectively, to the best model already selected in the first step, and changes in AIC were monitored. (Co)variances between traits were estimated using bivariate analyses. In Baluchi sheep, for BW, WW and W6, estimates of maternal imprinting heritability (${\boldsymbol h}_{{\boldsymbol mi}}^2$) were 0.12 ± 0.02, 0.08 ± 0.01 and 0.09 ± 0.01, respectively. In Makuie sheep, paternal imprinting heritability (${\boldsymbol h}_{{\boldsymbol pi}}^2$) for BW, WW, W6, GRb and KRb were 0.17 ± 0.05, 0.8 ± 0.05, 0.38 ± 0.10, 0.71 ± 0.15 and 0.65 ± 0.13, respectively. In Baluchi sheep, strong maternal imprinting correlations were observed between BW and WW (0.93 ± 0.05), BW and W6 (0.80 ± 0.07) and WW and W6 (0.91 ± 0.02). In Makuie sheep, paternal imprinting correlations ranged from −0.97 ± 0.33 (BW-GRb) to 0.99 ± 0.47 (GRb-KRb). It was concluded that imprinting effects need to be included in the statistical model to increase the accuracy of genetic evaluation. However, to have accurate and reliable estimates of imprinting effects, the availability of large data sets and deep pedigrees are necessary.

Epigenetic integrity of paternal imprints enhances the developmental potential of androgenetic haploid embryonic stem cells

The use of two inhibitors of Mek1/2 and Gsk3β (2i) promotes the generation of mouse diploid and haploid embryonic stem cells (ESCs) from the inner cell mass of biparental and uniparental blastocysts, respectively. However, a system enabling long-term maintenance of imprints in ESCs has proven challenging. Here, we report that the use of a two-step a2i (alternative two inhibitors of Src and Gsk3β, TSa2i) derivation/culture protocol results in the establishment of androgenetic haploid ESCs (AG-haESCs) with stable DNA methylation at paternal DMRs (differentially DNA methylated regions) up to passage 60 that can efficiently support generating mice upon oocyte injection. We also show coexistence of H3K9me3 marks and ZFP57 bindings with intact DMR methylations. Furthermore, we demonstrate that TSa2i-treated AG-haESCs are a heterogeneous cell population regarding paternal DMR methylation. Strikingly, AG-haESCs with late passages display increased paternal-DMR methylations and improved developmental potential compared to early-passage cells, in part through the enhanced proliferation of H19-DMR hypermethylated cells. Together, we establish AG-haESCs that can long-term maintain paternal imprints.

Generation of developmentally competent oocytes and fertile mice from parthenogenetic embryonic stem cells

Parthenogenetic embryos, created by activation and diploidization of oocytes, arrest at mid-gestation for defective paternal imprints, which impair placental development. Also, viable offspring has not been obtained without genetic manipulation from parthenogenetic embryonic stem cells (pESCs) derived from parthenogenetic embryos, presumably attributable to their aberrant imprinting. We show that an unlimited number of oocytes can be derived from pESCs and produce healthy offspring. Moreover, normal expression of imprinted genes is found in the germ cells and the mice. pESCs exhibited imprinting consistent with exclusively maternal lineage, and higher X-chromosome activation compared to female ESCs derived from the same mouse genetic background. pESCs differentiated into primordial germ cell-like cells (PGCLCs) and formed oocytes following in vivo transplantation into kidney capsule that produced fertile pups and reconstituted ovarian endocrine function. The transcriptome and methylation of imprinted and X-linked genes in pESC-PGCLCs closely resembled those of in vivo produced PGCs, consistent with efficient reprogramming of methylation and genomic imprinting. These results demonstrate that amplification of germ cells through parthenogenesis faithfully maintains maternal imprinting, offering a promising route for deriving functional oocytes and having potential in rebuilding ovarian endocrine function.

Investigation of age-related facial variation among Angelman syndrome patients

Angelman syndrome (AS) is one of the common genetic disorders that could emerge either from a 15q11–q13 deletion or paternal uniparental disomy (UPD) or imprinting or UBE3A mutations. AS comes with various behavioral and phenotypic variability, but the acquisition of subjects for experiment and automating the landmarking process to characterize facial morphology for Angelman syndrome variation investigation are common challenges. By automatically detecting and annotating subject faces, we collected 83 landmarks and 10 anthropometric linear distances were measured from 17 selected anatomical landmarks to account for shape variability. Statistical analyses were performed on the extracted data to investigate facial variation in each age group. There is a correspondence in the results achieved by relative warp (RW) of the principal component (PC) and the thin-plate spline (TPS) interpolation. The group is highly discriminated and the pattern of shape variability is higher in children than other groups when judged by the anthropometric measurement and principal component.

Derivation of Mouse Parthenogenetic Advanced Stem Cells.

Parthenogenetic embryos have been widely studied as an effective tool related to paternal and maternal imprinting genes and reproductive problems for a long time. In this study, we established a parthenogenetic epiblast-like stem cell line through culturing parthenogenetic diploid blastocysts in a chemically defined medium containing activin A and bFGF named paAFSCs. The paAFSCs expressed pluripotent marker genes and germ-layer-related genes, as well as being alkaline-phosphatase-positive, which is similar to epiblast stem cells (EpiSCs). We previously showed that advanced embryonic stem cells (ASCs) represent hypermethylated naive pluripotent embryonic stem cells (ESCs). Here, we converted paAFSCs to ASCs by replacing bFGF with bone morphogenetic protein 4 (BMP4), CHIR99021, and leukemia inhibitory factor (LIF) in a culture medium, and we obtained parthenogenetic advanced stem cells (paASCs). The paASCs showed similar morphology with ESCs and also displayed a stronger developmental potential than paAFSCs in vivo by producing chimaeras. Our study demonstrates that maternal genes could support parthenogenetic EpiSCs derived from blastocysts and also have the potential to convert primed state paAFSCs to naive state paASCs.

An N-ethyl-N-Nitrosourea Mutagenesis Screen in Mice Reveals a Mutation in Nuclear Respiratory Factor 1 (Nrf1) Altering the DNA Methylation State and Correct Embryonic Development.

Simple SummaryIn this work, we aimed to discover unknown genes that are important in the regulation of other genes. These genes often play an important role during the development of the embryo. By screening thousands of mice, we found a gene, namely, Nuclear Respiratory Factor 1 (Nrf1), that controls the switching on and off of other genes. Mice with a defective Nrf1 present lesser levels of the gene and embryonic delay. When the mutation is in both chains of the DNA, mice are not born and die in the uterus. Our work unveils a novel, previously unknown functionality of Nrf1 and provides a new mice model for the study of diseases caused by a defective Nrf1.We have established a genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen to identify novel genes playing a role in epigenetic regulation in mammals. We hypothesize that the ENU mutagenesis screen will lead to the discovery of unknown genes responsible of the maintenance of the epigenetic state as the genes found are modifiers of variegation of the transgene green fluorescent protein (GFP) expression in erythrocytes, which are named MommeD. Here we report the generation of a novel mutant mouse line, MommeD46, that carries a new missense mutation producing an amino acid transversion (L71P) in the dimerization domain of Nuclear Respiratory Factor 1 (Nrf1). The molecular characterization of the mutation reveals a decrease in the Nrf1 mRNA levels and a novel role of Nrf1 in the maintenance of the DNA hypomethylation in vivo. The heritability of the mutation is consistent with paternal imprinting and haploinsufficiency. Homozygous mutants display embryonic lethality at 14.5 days post-coitum and developmental delay. This work adds a new epi-regulatory role to Nrf1 and uncovers unknown phenotypical defects of the Nrf1 hypomorph. The generated mouse line represents a valuable resource for studying NRF1-related diseases.

Loss of p57 Expression in Conceptions Other Than Complete Hydatidiform Mole: A Case Series With Emphasis on the Etiology, Genetics, and Clinical Significance.

Combined p57 immunohistochemistry and DNA genotyping refines classification of products of conception specimens into specific types of hydatidiform moles and various nonmolar entities that can simulate them. p57 expression is highly correlated with genotyping and in practice can reliably be used to identify virtually all complete hydatidiform moles (CHM), but aberrant retained or lost p57 expression in rare CHMs and partial hydatidiform moles (PHM), as well as loss in some nonmolar abortuses, has been reported. Among a series of 2329 products of conceptions, we identified 10 cases for which loss of p57 expression was inconsistent with genotyping results (none purely androgenetic). They displayed a spectrum of generally mild abnormal villous morphology but lacked better developed features of CHMs/early CHMs, although some did suggest subtle forms of the latter. For 5 cases, genotyping (4 cases) and/or ancillary testing (1 case) determined a mechanism for the aberrant p57 results. These included 3 PHMs-2 diandric triploid and 1 triandric tetraploid-and 1 nonmolar specimen with loss of p57 expression attributable to partial or complete loss of the maternal copy of chromosome 11 and 1 nonmolar specimen with Beckwith-Wiedemann syndrome. For 5 cases, including 2 diandric triploid PHMs and 3 biparental nonmolar specimens, genotyping did not identify a mechanism, likely due to other genetic alterations which are below the resolution of or not targeted by genotyping. While overdiagnosis of a PHM as a CHM may cause less harm since appropriate follow-up with serum β-human chorionic gonadotropin levels would take place for both diagnoses, this could cause longer than necessary follow-up due to the expectation of a much greater risk of persistent gestational trophoblastic disease for CHM compared with PHM, which would be unfounded for the correct diagnosis of PHM. Overdiagnosis of a nonmolar abortus with loss of p57 expression as a CHM would lead to unnecessary follow-up and restriction on pregnancy attempts for patients with infertility. Genotyping is valuable for addressing discordance between p57 expression and morphology but cannot elucidate certain mechanisms of lost p57 expression. Future studies are warranted to determine whether chromosomal losses or gains, particularly involving imprinted genes such as p57, might play a role in modifying the risk of persistent gestational trophoblastic disease for PHMs and nonmolar conceptions that are not purely androgenetic but have some abnormal paternal imprinting of the type seen in CHMs.

Endosperm-based incompatibilities in hybrid monkeyflowers.

Endosperm is an angiosperm innovation central to their reproduction whose development, and thus seed viability, is controlled by genomic imprinting, where expression from certain genes is parent-specific. Unsuccessful imprinting has been linked to failed inter-specific and inter-ploidy hybridization. Despite their importance in plant speciation, the underlying mechanisms behind these endosperm-based barriers remain poorly understood. Here, we describe one such barrier between diploid Mimulus guttatus and tetraploid Mimulus luteus. The two parents differ in endosperm DNA methylation, expression dynamics, and imprinted genes. Hybrid seeds suffer from underdeveloped endosperm, reducing viability, or arrested endosperm and seed abortion when M. guttatus or M. luteus is seed parent, respectively, and transgressive methylation and expression patterns emerge. The two inherited M. luteus subgenomes, genetically distinct but epigenetically similar, are expressionally dominant over the M. guttatus genome in hybrid embryos and especially their endosperm, where paternal imprints are perturbed. In aborted seeds, de novo methylation is inhibited, potentially owing to incompatible paternal instructions of imbalanced dosage from M. guttatus imprints. We suggest that diverged epigenetic/regulatory landscapes between parental genomes induce epigenetic repatterning and global shifts in expression, which, in endosperm, may uniquely facilitate incompatible interactions between divergent imprinting schemes, potentially driving rapid barriers.

Humanization of a tandem repeat in IG-DMR causes stochastic restoration of paternal imprinting at mouse Dlk1-Dio3 domain.

The Dlk1-Dio3 imprinted domain, regulated by an intergenic differentially methylated region (IG-DMR), is important for mammalian embryonic development. Although previous studies have reported that DNA methylation of a tandem repeated array sequence in paternal IG-DMR (IG-DMR-Rep) plays an essential role in the maintenance of DNA methylation in mice, the function of a tandem repeated array sequence in human IG-DMR (hRep) is unknown. Here, we generated mice with a human tandem repeated sequence, which replaced the mouse IG-DMR-Rep. Mice that transmitted the humanized allele paternally exhibited variable methylation status at the IG-DMR and were stochastically rescued from the lethality of IG-DMR-Rep deficiency, suggesting that hRep plays a role in human IG-DMR for the regulation of imprinted expression. Moreover, chromatin immunoprecipitation analysis showed that TRIM28 was enriched in hypermethylated paternal hRep without ZFP57. Our results suggest that hRep contributes to the maintenance of human IG-DMR methylation imprints via the recruitment of TRIM28.