RESUMO
Imprinted gene clusters are confined genomic regions containing genes with parent-of-origin-dependent transcriptional activity. In this issue of Genes & Development, Loftus and colleagues (pp. 829-843) made use of an insightful combination of descriptive approaches, genetic manipulations, and epigenome-editing approaches to show that differences in nuclear topology precede the onset of imprinted expression at the Peg13-Kcnk9 locus. Furthermore, the investigators provide data in line with a model suggesting that parent-of-origin-specific topological differences could be responsible for parent-of-origin-specific enhancer activity and thus imprinted expression.
Assuntos
Metilação de DNA , Impressão GenômicaRESUMO
Differences in chromatin state inherited from the parental gametes influence the regulation of maternal and paternal alleles in offspring. This phenomenon, known as genomic imprinting, results in genes preferentially transcribed from one parental allele. While local epigenetic factors such as DNA methylation are known to be important for the establishment of imprinted gene expression, less is known about the mechanisms by which differentially methylated regions (DMRs) lead to differences in allelic expression across broad stretches of chromatin. Allele-specific higher-order chromatin structure has been observed at multiple imprinted loci, consistent with the observation of allelic binding of the chromatin-organizing factor CTCF at multiple DMRs. However, whether allelic chromatin structure impacts allelic gene expression is not known for most imprinted loci. Here we characterize the mechanisms underlying brain-specific imprinted expression of the Peg13-Kcnk9 locus, an imprinted region associated with intellectual disability. We performed region capture Hi-C on mouse brains from reciprocal hybrid crosses and found imprinted higher-order chromatin structure caused by the allelic binding of CTCF to the Peg13 DMR. Using an in vitro neuron differentiation system, we showed that imprinted chromatin structure precedes imprinted expression at the locus. Additionally, activation of a distal enhancer induced imprinted expression of Kcnk9 in an allelic chromatin structure-dependent manner. This work provides a high-resolution map of imprinted chromatin structure and demonstrates that chromatin state established in early development can promote imprinted expression upon differentiation.
Assuntos
Metilação de DNA , Impressão Genômica , Animais , Camundongos , Alelos , Metilação de DNA/genética , Impressão Genômica/genética , Cromatina , Neurogênese/genéticaRESUMO
Allele-specific expression of imprinted gene clusters is governed by gametic DNA methylation at master regulators called imprinting control regions (ICRs). Non-gametic or secondary differentially methylated regions (DMRs) at promoters and exonic regions reinforce monoallelic expression but do not control an entire cluster. Here, we unveil an unconventional secondary DMR that is indispensable for tissue-specific imprinting of two previously unlinked genes, Grb10 and Ddc. Using polymorphic mice, we mapped an intronic secondary DMR at Grb10 with paternal-specific CTCF binding (CBR2.3) that forms contacts with Ddc. Deletion of paternal CBR2.3 removed a critical insulator, resulting in substantial shifting of chromatin looping and ectopic enhancer-promoter contacts. Destabilized gene architecture precipitated abnormal Grb10-Ddc expression with developmental consequences in the heart and muscle. Thus, we redefine the Grb10-Ddc imprinting domain by uncovering an unconventional intronic secondary DMR that functions as an insulator to instruct the tissue-specific, monoallelic expression of multiple genes-a feature previously ICR exclusive.
Assuntos
Impressão Genômica , RNA Longo não Codificante , Alelos , Animais , Cromatina/genética , Metilação de DNA , Proteína Adaptadora GRB10/genética , Coração , CamundongosRESUMO
Genomic imprinting regulates parental origin-dependent monoallelic gene expression. It is mediated by either germline differential methylation of DNA (canonical imprinting) or oocyte-derived H3K27me3 (noncanonical imprinting) in mice. Depletion of Eed, an essential component of Polycomb repressive complex 2, results in genome-wide loss of H3K27me3 in oocytes, which causes loss of noncanonical imprinting (LOI) in embryos. Although Eed maternal KO (matKO) embryos show partial lethality after implantation, it is unknown whether LOI itself contributes to the developmental phenotypes of these embryos, which makes it unclear whether noncanonical imprinting is developmentally relevant. Here, by combinatorial matKO of Xist, a noncanonical imprinted gene whose LOI causes aberrant transient maternal X-chromosome inactivation (XCI) at preimplantation, we show that prevention of the transient maternal XCI greatly restores the development of Eed matKO embryos. Moreover, we found that the placentae of Eed matKO embryos are remarkably enlarged in a manner independent of Xist LOI. Heterozygous deletion screening of individual autosomal noncanonical imprinted genes suggests that LOI of the Sfmbt2 miRNA cluster chromosome 2 miRNA cluster (C2MC), solute carrier family 38 member 4 (Slc38a4), and Gm32885 contributes to the placental enlargement. Taken together, our study provides evidence that Xist imprinting sustains embryonic development and that autosomal noncanonical imprinting restrains placental overgrowth.
Assuntos
MicroRNAs , RNA Longo não Codificante , Animais , Desenvolvimento Embrionário/genética , Feminino , Histonas/metabolismo , Camundongos , Placenta , Gravidez , RNA Longo não Codificante/genética , Proteínas Repressoras/genética , Inativação do Cromossomo XRESUMO
Genomic imprinting is the monoallelic expression of a gene based on parent of origin and is a consequence of differential epigenetic marking between the male and female germlines. Canonically, genomic imprinting is mediated by allelic DNA methylation. However, recently it has been shown that maternal H3K27me3 can result in DNA methylation-independent imprinting, termed "noncanonical imprinting." In this review, we compare and contrast what is currently known about the underlying mechanisms, the role of endogenous retroviral elements, and the conservation of canonical and noncanonical genomic imprinting.
Assuntos
Impressão Genômica/fisiologia , Metilação de DNA , Epigenômica , Humanos , Retroelementos/genéticaRESUMO
In this perspective I look back on the twists and turns that influenced the direction of my scientific career over the past 40 years. From my early ambition to be a chemist to my training in Philadelphia and Bethesda as a molecular biologist, I benefited enormously from generous and valuable mentoring. In my independent career in Philadelphia and Princeton, I was motivated by a keen interest in the changes in gene expression that direct the development of the mammalian embryo and inspired by the creativity and energy of my students, fellows, and research staff. After twelve years as President of Princeton University, I have happily returned to the faculty of the Department of Molecular Biology.
Assuntos
Biologia Molecular/história , Universidades/história , Sequência de Aminoácidos , Animais , Canadá , Passeio de Cromossomo , Desenvolvimento Embrionário/genética , Proteínas do Olho/genética , Proteínas do Olho/história , Regulação da Expressão Gênica no Desenvolvimento , Impressão Genômica , História do Século XX , História do Século XXI , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/história , Humanos , Camundongos , Dados de Sequência Molecular , National Institutes of Health (U.S.) , New Jersey , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/história , Splicing de RNA , RNA Longo não Codificante/genética , RNA Longo não Codificante/história , Proteínas Repressoras/genética , Proteínas Repressoras/história , Estados Unidos , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/história , Globinas beta/genética , Globinas beta/históriaRESUMO
Imprinted genes with parental-biased allelic expression are frequently co-regulated and enriched in common biological pathways. Here, we functionally characterize a large cluster of microRNAs (miRNAs) expressed from the maternally inherited allele ("maternally expressed") to explore the molecular and cellular consequences of imprinted miRNA activity. Using an induced neuron (iN) culture system, we show that maternally expressed miRNAs from the miR-379/410 cluster direct the RNA-induced silencing complex (RISC) to transcriptional and developmental regulators, including paternally expressed transcripts like Plagl1. Maternal deletion of this imprinted miRNA cluster resulted in increased protein levels of several targets and upregulation of a broader transcriptional program regulating synaptic transmission and neuronal function. A subset of the transcriptional changes resulting from miR-379/410 deletion can be attributed to de-repression of Plagl1. These data suggest maternally expressed miRNAs antagonize paternally driven gene programs in neurons.
Assuntos
Impressão Genômica , MicroRNAs/metabolismo , Neurônios/metabolismo , Animais , Proteínas Argonautas/metabolismo , Linhagem Celular , Células Cultivadas , Células-Tronco Embrionárias/metabolismo , Potenciais Pós-Sinápticos Excitadores , Deleção de Genes , Camundongos , MicroRNAs/genética , Neurogênese/genética , Neurônios/fisiologia , Complexo de Inativação Induzido por RNA/metabolismo , Transmissão Sináptica/genética , Transcrição GênicaRESUMO
Genomic imprinting is an epigenetic phenomenon leading to parentally biased gene expression. Throughout the years, extensive efforts have been made to characterize the epigenetic marks underlying imprinting in animals and plants. As a result, DNA methylation asymmetries between parental genomes emerged as the primary factor controlling the imprinting status of many genes. Nevertheless, the data accumulated so far suggest that this process cannot solely explain the imprinting of all genes. In this review, we revisit the current models explaining imprinting regulation in plants, and discuss novel regulatory mechanisms that could function independently of parental DNA methylation asymmetries in the establishment of imprinting.
Assuntos
Impressão Genômica/genética , Modelos Genéticos , Plantas/genética , Metilação de DNARESUMO
Oocyte maturation and preimplantation embryo development are critical to successful pregnancy outcomes and the correct establishment and maintenance of genomic imprinting. Thanks to novel technologies and omics studies in human patients and mouse models, the importance of the proteins associated with the cytoplasmic lattices (CPLs), highly abundant structures found in the cytoplasm of mammalian oocytes and preimplantation embryos, in the maternal to zygotic transition is becoming increasingly evident. This review highlights the recent discoveries on the role of these proteins in protein storage and other oocyte cytoplasmic processes, epigenetic reprogramming, and zygotic genome activation (ZGA). A better comprehension of these events may significantly improve clinical diagnosis and pave the way for targeted interventions aiming to correct or mitigate female fertility issues and genomic imprinting disorders.
RESUMO
Nearly half of the human genome consists of endogenous retroelements (EREs) and their genetic remnants, a small fraction of which carry the potential to propagate in the host genome, posing a threat to genome integrity and cell/organismal survival. The largest family of transcription factors in tetrapods, the Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs), binds to specific EREs and represses their transcription. Since their first appearance over 400 million years ago, KRAB-ZFPs have undergone dramatic expansion and diversification in mammals, correlating with the invasions of new EREs. In this article we review our current understanding of the structure, function, and evolution of KRAB-ZFPs and discuss growing evidence that the arms race between KRAB-ZFPs and the EREs they target is a major driving force for the evolution of new traits in mammals, often accompanied by domestication of EREs themselves.
Assuntos
Imunidade Celular/fisiologia , Mamíferos/genética , Retroelementos , Dedos de Zinco/fisiologia , Animais , Regulação da Expressão Gênica , Impressão Genômica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Meiose , Família Multigênica , Domínios ProteicosRESUMO
Genomic imprinting is an epigenetic mechanism by which genes are expressed in a parental origin-dependent manner. We recently discovered that, like DNA methylation, oocyte-inherited H3K27me3 can also serve as an imprinting mark in mouse preimplantation embryos. In this study, we found H3K27me3 is strongly biased toward the maternal allele with some associated with DNA methylation-independent paternally expressed genes (PEGs) in human morulae. The H3K27me3 domains largely overlap with DNA partially methylated domains (PMDs) and occupy developmental gene promoters. Thus, our study not only reveals the H3K27me3 landscape but also establishes a correlation between maternal-biased H3K27me3 and PEGs in human morulae.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Impressão Genômica/genética , Histonas/metabolismo , Mórula/fisiologia , Alelos , Metilação de DNA , Feminino , Histonas/genética , Humanos , Masculino , Regiões Promotoras Genéticas/genéticaRESUMO
Adult neurogenesis is supported by multipotent neural stem cells (NSCs) with unique properties and growth requirements. Adult NSCs constitute a reversibly quiescent cell population that can be activated by extracellular signals from the microenvironment in which they reside in vivo. Although genomic imprinting plays a role in adult neurogenesis through dose regulation of some relevant signals, the roles of many imprinted genes in the process remain elusive. Insulin-like growth factor 2 (IGF2) is encoded by an imprinted gene that contributes to NSC maintenance in the adult subventricular zone through a biallelic expression in only the vascular compartment. We show here that IGF2 additionally promotes terminal differentiation of NSCs into astrocytes, neurons and oligodendrocytes by inducing the expression of the maternally expressed gene cyclin-dependent kinase inhibitor 1c (Cdkn1c), encoding the cell cycle inhibitor p57. Using intraventricular infusion of recombinant IGF2 in a conditional mutant strain with Cdkn1c-deficient NSCs, we confirm that p57 partially mediates the differentiation effects of IGF2 in NSCs and that this occurs independently of its role in cell-cycle progression, balancing the relationship between astrogliogenesis, neurogenesis and oligodendrogenesis.
Assuntos
Inibidor de Quinase Dependente de Ciclina p57 , Impressão Genômica , Fator de Crescimento Insulin-Like II , Células-Tronco Neurais , Neurogênese , Neurônios , Inibidor de Quinase Dependente de Ciclina p57/genética , Células-Tronco Neurais/citologia , Neurônios/citologia , Neurogênese/genética , Fator de Crescimento Insulin-Like II/genética , Animais , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Genomic imprinting is essential for mammalian development. Recent studies have revealed that maternal histone H3 Lys27 trimethylation (H3K27me3) can mediate DNA methylation-independent genomic imprinting. However, the regulatory mechanisms and functions of this new imprinting mechanism are largely unknown. Here we demonstrate that maternal Eed, an essential component of the Polycomb group complex 2 (PRC2), is required for establishing H3K27me3 imprinting. We found that all H3K27me3-imprinted genes, including Xist, lose their imprinted expression in Eed maternal knockout (matKO) embryos, resulting in male-biased lethality. Surprisingly, although maternal X-chromosome inactivation (XmCI) occurs in Eed matKO embryos at preimplantation due to loss of Xist imprinting, it is resolved at peri-implantation. Ultimately, both X chromosomes are reactivated in the embryonic cell lineage prior to random XCI, and only a single X chromosome undergoes random XCI in the extraembryonic cell lineage. Thus, our study not only demonstrates an essential role of Eed in H3K27me3 imprinting establishment but also reveals a unique XCI dynamic in the absence of Xist imprinting.
Assuntos
Impressão Genômica/genética , Histonas/metabolismo , Complexo Repressor Polycomb 2/genética , Inativação do Cromossomo X/genética , Animais , Linhagem da Célula , Implantação do Embrião/genética , Embrião de Mamíferos , Feminino , Técnicas de Inativação de Genes , Histonas/genética , Masculino , Metilação , Camundongos , Camundongos KnockoutRESUMO
Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR), but the underlying mechanism remains largely unclear. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and mutation of human Naa10p is linked to severe developmental delays. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorders, and maternal effect lethality, phenotypes commonly observed in defective genomic imprinting. Genome-wide analyses further revealed global DNA hypomethylation and enriched dysregulation of imprinted genes in Naa10p-knockout embryos and embryonic stem cells. Mechanistically, Naa10p facilitates binding of DNA methyltransferase 1 (Dnmt1) to DNA substrates, including the ICRs of the imprinted allele during S phase. Moreover, the lethal Ogden syndrome-associated mutation of human Naa10p disrupts its binding to the ICR of H19 and Dnmt1 recruitment. Our study thus links Naa10p mutation-associated Ogden syndrome to defective DNA methylation and genomic imprinting.
Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Deficiências do Desenvolvimento/genética , Epigênese Genética , Impressão Genômica , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética , RNA Longo não Codificante/genética , Animais , DNA/genética , DNA/metabolismo , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Deleção de Genes , Genes Letais , Estudo de Associação Genômica Ampla , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/patologia , Acetiltransferase N-Terminal A/deficiência , Acetiltransferase N-Terminal E/deficiência , Ligação Proteica , RNA Longo não Codificante/metabolismo , Fase S/genéticaRESUMO
In mammals, a new life starts with the fusion of an oocyte and asperm cell. Parthenogenesis, a way of generating offspring solelyfrom female gametes, is limited because of problems arising fromgenomic imprinting. Here, we report live mammalian offspringderived from single unfertilized oocytes, which was achieved by tar-geted DNA methylation rewriting of seven imprinting control regions.Oocyte coinjection of catalytically inactive Cas9 (dCas9)-Dnmt3a ordCpf1-Tet1 messenger RNA (mRNA) with single-guide RNAs (sgRNAs)targeting specific regions induced de novo methylation or demethyla-tion, respectively, of the targeted region. Following parthenogeneticactivation, these edited regions showed maintenance of methylationas naturally established regions during early preimplantation develop-ment. The transfer of modified parthenogenetic embryos into fostermothers resulted in significantly extended development andfinally inthe generation of viable full-term offspring. These data demonstratethat parthenogenesis can be achieved by targeted epigenetic rewrit-ing of multiple critical imprinting control regions.
Assuntos
Metilação de DNA , Impressão Genômica , Animais , Mamíferos/genética , Oócitos/metabolismo , PartenogêneseRESUMO
BACKGROUND: Optimal size at birth dictates perinatal survival and long-term risk of developing common disorders such as obesity, type 2 diabetes and cardiovascular disease. The imprinted Grb10 gene encodes a signalling adaptor protein capable of inhibiting receptor tyrosine kinases, including the insulin receptor (Insr) and insulin-like growth factor type 1 receptor (Igf1r). Grb10 restricts fetal growth such that Grb10 knockout (KO) mice are at birth some 25-35% larger than wild type. Using a mouse genetic approach, we test the widely held assumption that Grb10 influences growth through interaction with Igf1r, which has a highly conserved growth promoting role. RESULTS: Should Grb10 interact with Igf1r to regulate growth Grb10:Igf1r double mutant mice should be indistinguishable from Igf1r KO single mutants, which are around half normal size at birth. Instead, Grb10:Igf1r double mutants were intermediate in size between Grb10 KO and Igf1r KO single mutants, indicating additive effects of the two signalling proteins having opposite actions in separate pathways. Some organs examined followed a similar pattern, though Grb10 KO neonates exhibited sparing of the brain and kidneys, whereas the influence of Igf1r extended to all organs. An interaction between Grb10 and Insr was similarly investigated. While there was no general evidence for a major interaction for fetal growth regulation, the liver was an exception. The liver in Grb10 KO mutants was disproportionately overgrown with evidence of excess lipid storage in hepatocytes, whereas Grb10:Insr double mutants were indistinguishable from Insr single mutants or wild types. CONCLUSIONS: Grb10 acts largely independently of Igf1r or Insr to control fetal growth and has a more variable influence on individual organs. Only the disproportionate overgrowth and excess lipid storage seen in the Grb10 KO neonatal liver can be explained through an interaction between Grb10 and the Insr. Our findings are important for understanding how positive and negative influences on fetal growth dictate size and tissue proportions at birth.
Assuntos
Desenvolvimento Fetal , Proteína Adaptadora GRB10 , Camundongos Knockout , Receptor IGF Tipo 1 , Receptor de Insulina , Animais , Proteína Adaptadora GRB10/genética , Proteína Adaptadora GRB10/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Camundongos , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Desenvolvimento Fetal/genética , Impressão Genômica , Feminino , Masculino , Peptídeos Semelhantes à InsulinaRESUMO
Maternal imprinting at the Xist gene is essential to achieve paternal allele-specific imprinted X-chromosome inactivation (XCI) in female mammals. However, the mechanism underlying Xist imprinting is unclear. Here we show that the Xist locus is coated with a broad H3K27me3 domain that is established during oocyte growth and persists through preimplantation development in mice. Loss of maternal H3K27me3 induces maternal Xist expression and maternal XCI in preimplantation embryos. Our study thus identifies maternal H3K27me3 as the imprinting mark of Xist.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Impressão Genômica/genética , Histona-Lisina N-Metiltransferase/metabolismo , RNA Longo não Codificante/genética , Inativação do Cromossomo X/genética , Animais , Blastocisto , Embrião de Mamíferos , Feminino , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/genética , Masculino , Camundongos , Oocistos/fisiologiaRESUMO
Mosaicism refers to the presence of genetically distinct cell populations in an individual derived from a single zygote, which occurs during the process of development, aging, and genetic diseases. To date, a variety of genetically engineered mosaic analysis models have been established and widely used in studying gene function at exceptional cellular and spatiotemporal resolution, leading to many ground-breaking discoveries. Mosaic analysis with a repressible cellular marker and mosaic analysis with double markers are genetic mosaic analysis models based on trans-recombination. These models can generate sibling cells of distinct genotypes in the same animal and simultaneously label them with different colors. As a result, they offer a powerful approach for lineage tracing and studying the behavior of individual mutant cells in a wildtype environment, which is particularly useful for determining whether gene function is cell autonomous or nonautonomous. Here, we present a comprehensive review on the establishment and applications of mosaic analysis with a repressible cellular marker and mosaic analysis with double marker systems. Leveraging the capabilities of these mosaic models for phenotypic analysis will facilitate new discoveries on the cellular and molecular mechanisms of development and disease.
Assuntos
Mosaicismo , Recombinação Genética , Animais , Genótipo , Fenótipo , HumanosRESUMO
Using a new method for bulk preparation of early stage embryos, we have investigated the role played by putative Planococcus citri H3K9 and H4K20 histone methyl transferases (HMTases) in regulating heterochromatinization of the imprinted paternal chromosomal set in male embryos. We found that H3K9 and H420 HMTases are required for heterochromatinization of the paternal chromosomes. We present evidence that both HMTases maintain the paternal "imprint" during the cleavage divisions when both parental chromosome sets are euchromatic. A testable model that accommodates our findings is proposed.
Assuntos
Heterocromatina , Metiltransferases , Masculino , Humanos , Metiltransferases/genética , Heterocromatina/genética , Histonas/genéticaRESUMO
Genomic imprinting is a parent-of-origin-specific expression phenomenon that plays fundamental roles in many biological processes. In animals, imprinting is only observed in therian mammals, with â¼200 imprinted genes known in humans and mice. The imprinting pattern in marsupials has been minimally investigated by examining orthologs to known eutherian imprinted genes. To identify marsupial-specific imprinting in an unbiased way, we performed RNA-seq studies on samples of fetal brain and placenta from the reciprocal cross progeny of two laboratory opossum stocks. We inferred allele-specific expression for >3,000 expressed genes and discovered/validated 13 imprinted genes, including three previously known imprinted genes, Igf2r, Peg10, and H19. We estimate that marsupials imprint â¼60 autosomal genes, which is a much smaller set compared with eutherians. Among the nine novel imprinted genes, three noncoding RNAs have no known homologs in eutherian mammals, while the remaining genes have important functions in pluripotency, transcription regulation, nucleolar homeostasis, and neural differentiation. Methylation analyses at promoter CpG islands revealed differentially methylated regions in five of these marsupial-specific imprinted genes, suggesting that differential methylation is a common mechanism in the epigenetic regulation of marsupial imprinting. Clustering and co-regulation were observed at marsupial imprinting loci Pou5f3-Npdc1 and Nkrfl-Ipncr2, but eutherian-type multi-gene imprinting clusters were not detected. Also differing from eutherian mammals, the brain and placenta imprinting profiles are remarkably similar in opossums, presumably due to the shared origin of these organs from the trophectoderm. Our results contribute to a fuller understanding of the origin, evolution, and mechanisms of genomic imprinting in therian mammals.