The Rodent-Specific MicroRNA Cluster within the Sfmbt2 Gene Is Imprinted and Essential for Placental Development
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE82055 | GEO | 2017/02/01
SECONDARY ACCESSION(S): PRJNA323829
REPOSITORIES: GEO
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Project description:MicroRNAs (miRNAs) represent small noncoding RNAs that are involved in physiologic and developmental processes by negatively regulating expression of target genes. They exist as individual miRNA genes or as polycistronically transcribed gene clusters. The largest miRNA cluster in mice is located in intron 10 of the Sfmbt2 gene, and contains 72 miRNA precursor sequences within approximately 50 kb. Although this miRNA cluster emerged recently in the rodent genome, probably coincidentally with the acquisition of the imprinted control of Sfmbt2, very little is known about its functions. In this study, we generated mice lacking the entire Sfmbt2 miRNA cluster to elucidate its functions during development. Like the Sfmbt2 gene, the Sfmbt2 miRNAs were expressed in the placenta predominantly from the paternal allele. Loss of the paternal allele resulted in severely impaired development of the spongiotrophoblast layer, which usually comprises about half of the fetal placenta. This phenotype was associated with fetal developmental delay or lethality, leading to significant decreases in the number of fetuses and their weights at term. Microarray analysis identified that at least 30 miRNAs in the cluster were actively transcribed in wild-type placentas. Among the predicted targets of these miRNAs, 132 genes were upregulated in the miRNA-deleted placentas. Some of the genes most significantly upregulated, including Gkn2 and Runx1, are known to inhibit cell proliferation by inducing cell cycle arrest or apoptosis. Thus, the Sfmbt2 miRNAs play essential roles in promoting trophoblastic cell proliferation in the placenta, cooperating with the host gene under the same paternal expression control.
2017-02-01 | GSE82054 | GEO
Project description:MicroRNAs (miRNAs) represent small noncoding RNAs that are involved in physiologic and developmental processes by negatively regulating expression of target genes. They exist as individual miRNA genes or as polycistronically transcribed gene clusters. The largest miRNA cluster in mice is located in intron 10 of the Sfmbt2 gene, and contains 72 miRNA precursor sequences within approximately 50 kb. Although this miRNA cluster emerged recently in the rodent genome, probably coincidentally with the acquisition of the imprinted control of Sfmbt2, very little is known about its functions. In this study, we generated mice lacking the entire Sfmbt2 miRNA cluster to elucidate its functions during development. Like the Sfmbt2 gene, the Sfmbt2 miRNAs were expressed in the placenta predominantly from the paternal allele. Loss of the paternal allele resulted in severely impaired development of the spongiotrophoblast layer, which usually comprises about half of the fetal placenta. This phenotype was associated with fetal developmental delay or lethality, leading to significant decreases in the number of fetuses and their weights at term. Microarray analysis identified that at least 30 miRNAs in the cluster were actively transcribed in wild-type placentas. Among the predicted targets of these miRNAs, 132 genes were upregulated in the miRNA-deleted placentas. Some of the genes most significantly upregulated, including Gkn2 and Runx1, are known to inhibit cell proliferation by inducing cell cycle arrest or apoptosis. Thus, the Sfmbt2 miRNAs play essential roles in promoting trophoblastic cell proliferation in the placenta, cooperating with the host gene under the same paternal expression control.
2017-02-01 | GSE82053 | GEO
Project description:MicroRNAs (miRNAs) represent small noncoding RNAs that are involved in physiologic and developmental processes by negatively regulating expression of target genes. They exist as individual miRNA genes or as polycistronically transcribed gene clusters. The largest miRNA cluster in mice is located in intron 10 of the Sfmbt2 gene, and contains 72 miRNA precursor sequences within approximately 50 kb. Although this miRNA cluster emerged recently in the rodent genome, probably coincidentally with the acquisition of the imprinted control of Sfmbt2, very little is known about its functions. In this study, we generated mice lacking the entire Sfmbt2 miRNA cluster to elucidate its functions during development. Like the Sfmbt2 gene, the Sfmbt2 miRNAs were expressed in the placenta predominantly from the paternal allele. Loss of the paternal allele resulted in severely impaired development of the spongiotrophoblast layer, which usually comprises about half of the fetal placenta. This phenotype was associated with fetal developmental delay or lethality, leading to significant decreases in the number of fetuses and their weights at term. Microarray analysis identified that at least 30 miRNAs in the cluster were actively transcribed in wild-type placentas. Among the predicted targets of these miRNAs, 132 genes were upregulated in the miRNA-deleted placentas. Some of the genes most significantly upregulated, including Gkn2 and Runx1, are known to inhibit cell proliferation by inducing cell cycle arrest or apoptosis. Thus, the Sfmbt2 miRNAs play essential roles in promoting trophoblastic cell proliferation in the placenta, cooperating with the host gene under the same paternal expression control.
2017-02-01 | GSE87302 | GEO
Project description:The Rodent-Specific MicroRNA Cluster within the Sfmbt2 Gene Is Imprinted and Essential for Placental Development
| PRJNA323829 | ENA
Project description:BackgroundThe total number of miRNA genes in a genome, expression of which is responsible for the miRNA repertoire of an organism, is not precisely known. Moreover, the question of how new miRNA genes arise during evolution is incompletely understood. Recent data in humans and opossum indicate that retrotranspons of the class of short interspersed nuclear elements have contributed to the growth of microRNA gene clusters.MethodWe studied a large miRNA gene cluster in intron 10 of the mouse Sfmbt2 gene using bioinformatic tools.ResultsMice and rats are unique to harbor a 55-65 Kb DNA sequence in intron 10 of the Sfmbt2 gene. This intronic region is rich in regularly repeated B1 retrotransposons together with inverted self-complementary CA/TG microsatellites. The smallest repeats unit, called MSHORT1 in the mouse, was duplicated 9 times in a tandem head-to-tail array to form 2.5 Kb MLONG1 units. The center of the mouse miRNA gene cluster consists of 13 copies of MLONG1. BLAST analysis of MSHORT1 in the mouse shows that the repeat unit is unique for intron 10 of the Sfmbt2 gene and suggest a dual phase model for growth of the miRNA gene cluster:arrangement [corrected] of 10 MSHORT1 units into MLONG1 and further duplication of 13 head-to-tail MLONG1 units in the center of the miRNA gene cluster. Rats have a similar arrangement [corrected] of repeat units in intron 10 of the Sfmbt2 gene. The discrepancy between 65 miRNA genes in the mouse cluster as compared to only 1 miRNA gene in the corresponding rat repeat cluster is ascribed to sequence differences between MSHORT1 and RSHORT1 that result in lateral-shifted, less-stable miRNA precursor hairpins for RSHORT1.ConclusionOur data provides new evidence for the emerging concept that lineage-specific retroposons have played an important role in the birth of new miRNA genes during evolution. The large difference in the number of miRNA genes in two closely related species (65 versus 1, mice versus rats) indicates that this species-specific evolution can be a rapid process.
| S-EPMC3212979 | biostudies-literature
Project description:Imprinted genes play important roles in placenta development and function. Parthenogenetic embryos, deficient in paternally expressed imprinted genes, lack extra-embryonic tissues of the trophoblast lineage. Parthenogenetic trophoblast stem cells (TSCs) are extremely difficult to derive, suggesting that an imprinted gene(s) is necessary for TSC establishment or maintenance. In a candidate study, we were able to narrow the list to one known paternally expressed gene, Sfmbt2. We show that mouse embryos inheriting a paternal Sfmbt2 gene trap null allele have severely reduced placentae and die before E12.5 due to reduction of all trophoblast cell types. We infected early embryos with lentivirus vectors expressing anti-Sfmbt2 shRNAs and found that TSC derivation was significantly reduced. Together, these observations support the hypothesis that loss of SFMBT2 results in defects in maintenance of trophoblast cell types necessary for development of the extra-embryonic tissues, the placenta in particular.
| S-EPMC3817938 | biostudies-literature
Project description:Aberrant synaptic function is thought to underlie social deficits in neurodevelopmental disorders such as autism and schizophrenia. Although microRNAs have been shown to regulate synapse development and plasticity, their potential involvement in the control of social behaviour in mammals remains unexplored. Here, we show that deletion of the placental mammal-specific miR379-410 cluster in mice leads to hypersocial behaviour, which is accompanied by increased excitatory synaptic transmission, and exaggerated expression of ionotropic glutamate receptor complexes in the hippocampus. Bioinformatic analyses further allowed us to identify five "hub" microRNAs whose deletion accounts largely for the upregulation of excitatory synaptic genes observed, including Cnih2, Dlgap3, Prr7 and Src. Thus, the miR379-410 cluster acts a natural brake for sociability, and interfering with specific members of this cluster could represent a therapeutic strategy for the treatment of social deficits in neurodevelopmental disorders.
| S-EPMC6362351 | biostudies-literature
Project description:Differential marking of genes in female and male gametes by DNA methylation is essential to genomic imprinting. In female gametes transcription traversing differentially methylated regions (DMRs) is a common requirement for de novo methylation at DMRs. At the imprinted Gnas cluster oocyte specific transcription of a protein-coding transcript, Nesp, is needed for methylation of two DMRs intragenic to Nesp, namely the Nespas-Gnasxl DMR and the Exon1A DMR, thereby enabling expression of the Gnas transcript and repression of the Gnasxl transcript. On the paternal allele, Nesp is repressed, the germline DMRs are unmethylated, Gnas is repressed and Gnasxl is expressed. Using mutant mouse models, we show that on the paternal allele, ectopic transcription of Nesp traversing the intragenic Exon1A DMR (which regulates Gnas expression) results in de novo methylation of the Exon1A DMR and de-repression of Gnas just as on the maternal allele. However, unlike the maternal allele, methylation on the mutant paternal allele occurs post-fertilisation, i.e. in somatic cells. This, to our knowledge is the first example of transcript/transcription driven DNA methylation of an intragenic CpG island, in somatic tissues, suggesting that transcription driven de novo methylation is not restricted to the germline in the mouse. Additionally, Gnasxl is repressed on a paternal chromosome on which Nesp is ectopically expressed. Thus, a paternally inherited Gnas cluster showing ectopic expression of Nesp is "maternalised" in terms of Gnasxl and Gnas expression. We show that these mice have a phenotype similar to mutants with two expressed doses of Gnas and none of Gnasxl.
| S-EPMC4319783 | biostudies-literature
Project description:microRNAs (or miRNAs) are small noncoding RNAs (21 to 25 nucleotides) that are processed from longer hairpin RNA precursors and are believed to be involved in a wide range of developmental and cellular processes, by either repressing translation or triggering mRNA degradation (RNA interference). By using a computer-assisted approach, we have identified 46 potential miRNA genes located in the human imprinted 14q32 domain, 40 of which are organized as a large cluster. Although some of these clustered miRNA genes appear to be encoded by a single-copy DNA sequence, most of them are arranged in tandem arrays of closely related sequences. In the mouse, this miRNA gene cluster is conserved at the homologous distal 12 region. In vivo all the miRNAs that we have detected are expressed in the developing embryo (both in the head and in the trunk) and in the placenta, whereas in the adult their expression is mainly restricted to the brain. We also show that the miRNA genes are only expressed from the maternally inherited chromosome and that their imprinted expression is regulated by an intergenic germline-derived differentially methylated region (IG-DMR) located approximately 200 kb upstream from the miRNA cluster. The functions of these miRNAs, which seem only conserved in mammals, are discussed both in terms of epigenetic control and gene regulation during development.
| S-EPMC515320 | biostudies-literature
Project description:BackgroundPrenatal cadmium (Cd) exposure has been recognized to restrict growth, and male and female fetuses may have differential susceptibility to the developmental toxicity of Cd. Imprinted genes, which exhibit monoallelic expression based on parent of origin, are highly expressed in placental tissues. The function of these genes is particularly critical to fetal growth and development, and some are expressed in sex-specific patterns.ObjectivesWe aimed to examine whether prenatal Cd associates with the expression of imprinted placental genes, overall or in fetal sex-specific patterns, across two independent epidemiologic studies.MethodsWe tested for Cd–sex interactions in association with gene expression, then regressed the placental expression levels of 74 putative imprinted genes on placental log-Cd concentrations while adjusting for maternal age, sex, smoking history, and educational attainment. These models were performed within study- and sex-specific strata in the New Hampshire Birth Cohort Study (NHBCS; [Formula: see text]) and the Rhode Island Child Health Study (RICHS; [Formula: see text]). We then used fixed-effects models to estimate the sex-specific and overall associations across strata and then examine heterogeneity in the associations by fetal sex.ResultsWe observed that higher Cd concentrations were associated with higher expression of distal-less homeobox 5 (DLX5) ([Formula: see text]), and lower expression of h19 imprinted maternally expressed transcript (H19) ([Formula: see text]) and necdin, MAGE family member (NDN) ([Formula: see text]) across study and sex-specific strata, while three other genes [carboxypeptidase A4 (CPA4), growth factor receptor bound protein 10 (GRB10), and integrin-linked kinase (ILK)] were significantly associated with Cd concentrations, but only among female placenta ([Formula: see text]). Additionally, the expression of DLX5, H19, and NDN, the most statistically significant Cd-associated genes, were also associated with standardized birth weight z-scores.DiscussionThe differential regulation of a set of imprinted genes, particularly DLX5, H19, and NDN, in association with prenatal Cd exposure may be involved in overall developmental toxicity, and some imprinted genes may respond to Cd exposure in a manner that is specific to infant gender. https://doi.org/10.1289/EHP4264.
| S-EPMC6791491 | biostudies-literature