Non-canonical imprinting ensures embryonic development and restrains placental overgrowth
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA818529 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18428449.fastq.gz | Fastqsanger.gz | |||
| SRR18428450.fastq.gz | Fastqsanger.gz | |||
| SRR18428451.fastq.gz | Fastqsanger.gz | |||
| SRR18428452.fastq.gz | Fastqsanger.gz | |||
| SRR18428453.fastq.gz | Fastqsanger.gz |
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Project description:Genomic imprinting regulates parental origin-dependent mono-allelic gene expression. It is mediated by either germline differential methylation of DNA (canonical imprinting) or oocyte-derived H3K27me3 (non-canonical 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 non-canonical 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 non-canonical imprinting is developmentally relevant. Here, by combinatorial matKO of Xist, a non-canonical 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 find that the placentae of Eed matKO embryos are remarkably enlarged in a manner independent of Xist LOI. Heterozygous deletion screening of individual autosomal non-canonical 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 autosomal non-canonical imprinting restrains placental overgrowth.
2022-06-30 | GSE199115 | GEO
Project description:Embryos generated with the use of assisted reproductive technologies (ART) can develop overgrowth syndromes. In ruminants, the condition is referred to as large offspring syndrome (LOS) and exhibits variable phenotypic abnormalities including overgrowth, enlarged tongue, and abdominal wall defects. These characteristics recapitulate those observed in the human loss-of-imprinting (LOI) overgrowth syndrome Beckwith-Wiedemann (BWS). We have recently shown LOI at the KCNQ1 locus in LOS, the most common epimutation in BWS. Although the first case of ART-induced LOS was reported in 1995, studies have not yet determined the extent of LOI in this condition. Here, we determined allele-specific expression of imprinted genes previously identified in human and/or mouse in day 105 Bos taurus indicus X Bos taurus taurus F1 hybrid control and LOS fetuses using RNAseq. Our analysis allowed us to determine the monoallelic expression of 20 genes in tissues of control fetuses. LOS fetuses displayed variable LOI when compared to controls. Biallelic expression of imprinted genes in LOS was associated with tissue-specific hypomethylation of the normally methylated parental allele. In addition, a positive correlation was observed between bodyweight and the number of biallelically expressed imprinted genes in LOS fetuses. Further, not only was there loss of allele-specific expression of imprinted genes in LOS, but we also observed differential transcript amounts of these genes between control and overgrown fetuses. In summary, we characterized previously unidentified imprinted genes in bovine and identified misregulation of imprinting at multiple loci in LOS. We concluded that LOS is a multi-locus loss-of-imprinting syndrome, as is BWS.
2015-03-06 | GSE63509 | GEO
Project description:Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to growth and developmental changes in mouse offspring. In this study, we show that offspring from mouse oocytes lacking the PRC2 protein Embryonic Ectoderm Development (EED) were initially developmentally delayed, characterised by low blastocyst cell counts and substantial growth delay in mid-gestation embryos. This initial developmental delay was resolved as offspring underwent accelerated fetal development and growth in late gestation resulting in offspring that were similar stage and weight to controls at birth. The accelerated development and growth in offspring from Eed-null oocytes was associated with remodelling of the placenta, which involved an increase in fetal and maternal tissue size, conspicuous expansion of the glycogen enriched cell population and delayed parturition. Despite placental remodelling and accelerated offspring fetal growth and development, placental efficiency and fetal blood glucose levels were low, and the fetal blood metabolome was unchanged. Moreover, while expression of the H3K27me3-imprinted gene and amino acid transporter Slc38a4 was increased, fetal blood levels of individual amino acids were similar to controls, indicating that placental amino acid transport was not enhanced. Genome-wide analyses identified extensive transcriptional dysregulation and DNA methylation changes in affected placentas, including a range of imprinted and non-imprinted genes. Together, while deletion of Eed in growing oocytes resulted in fetal growth and developmental delay and placental hyperplasia, our data indicate a remarkable capacity for offspring fetal growth to be normalised despite inefficient placental function and the loss of H3K27me3-dependent genomic imprinting.
2024-01-26 | GSE210398 | GEO
Project description:Placenta hyperplasia is commonly observed in cloned animals and is believed to impede the proper development of cloned embryos. However, the mechanism underlying this phenomenon is largely unknown. Here we show that placenta hyperplasia of cloned mouse embryos occurs in both middle and late gestation. Interestingly, restoring paternal-specific expression of an amino acid transporter Slc38a4, which loses maternal H3K27me3-dependent imprinting and becomes bi-allelically expressed in cloned placentae, rescued the overgrowth of cloned placentae at late gestation. Molecular analyses reveal that loss of Slc38a4 imprinting leads to over activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in cloned placentae, which is likely due to the increased amino acids transportation by SLC38A4. Collectively, our study not only reveals loss of Slc38a4 imprinting is responsible for overgrowth of cloned placentae at late gestation, but also suggests the underlying mechanism involves increased amino acid transportation and over activation of mTORC1.
2022-01-20 | GSE174174 | GEO
Project description:This study aims to identify genome-wide placental DNA differential methylation positions (DMPs) in fetal overgrowth and the associations with fetal growth factors, leptin and adiponectin. In the Shanghai Birth Cohort, we studied 30 pairs of placentals of large-for-gestational-age (LGA, birth weight>90th percentile, an indicator of fetal overgrowth) and optimal-for-gestational-age (OGA, 25th-75th percentiles, control) newborns matched by sex and gestational age. Placental DNA methylations were measured by the Illumina Infinium Human Methylation-EPIC BeadChip. Cord blood insulin, C-peptide, proinsulin, IGF-1, IGF-2, leptin and adiponectin concentrations were measured. We identified 543 DMPs (397 hypermethylated, 146 hypomethylated) comparing LGA vs. OGA at false discovery rate <5% and absolute methylation difference >0.05 adjusting for placental cell type heterogeneity, maternal age, pre-pregnancy BMI and HbA1c levels during pregnancy. We validated a hyper-methylated gene - cadherin 13 (CDH13) reported in a previous epigenome-wide association study, and validated a newly discovered differentially (hyper-)methylated gene -visual system homeobox 1 (VSX1) in an independent pyrosequencing study sample (47 LGA-control pairs). Pathway analysis did not detect any statistically significant pathway correcting for multiple tests. Adiponectin in cord blood was correlated with its gene methylation in the placenta, while other observed biomarkers were not. Fetal overgrowth was associated with a large number of altered placental gene DNA methylations. The study provides robust evidence suggesting that placental CDH13 and VSX1 genes are hyper-methylated in LGA. Placental gene methylation was correlated with cord blood biomarker for adiponectin, but not for leptin and fetal growth factors.
2022-12-31 | GSE204977 | GEO
Project description:Background: Genomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on parent-of-origin, and is typically regulated by differential DNA methylation inherited from gametes. Imprinting is pervasive in murine extra-embryonic lineages and, uniquely, the imprinting of several genes has been found to be conferred non-canonically through maternally-inherited repressive histone modification H3K27me3. However, the underlying regulatory mechanisms of non-canonical imprinting in post-implantation development remain unexplored. Results: We identify imprinted regions in post-implantation epiblast and extra-embryonic ectoderm (ExE) by assaying allelic histone modifications (H3K4me3, H3K36me3, H3K27me3), gene expression and DNA methylation in reciprocal C57BL/6 and CAST hybrid embryos. We distinguish loci with DNA methylation- dependent (canonical) and independent (non-canonical) imprinting by assaying hybrid embryos with ablated maternally-inherited DNA methylation. We find that non-canonical imprints are localized to endogenous retrovirus-K (ERVK) long terminal repeats (LTRs), which act as imprinted promoters specifically in extra-embryonic lineages. Transcribed ERVK LTRs are CpG-rich and located in close proximity to gene promoters, and imprinting status is determined by their epigenetic patterning in the oocyte. Finally, we show that oocyte-derived H3K27me3 associates with non-canonical imprints is not maintained beyond pre-implantation development, and is replaced by secondary imprinted DNA methylation on the maternal allele in post-implantation ExE, while being completely silenced by bi-allelic DNA methylation in epiblast. Conclusions: This study reveals distinct epigenetic mechanisms regulating non-canonical imprinted gene expression between embryonic and extra-embryonic development, and identifies an integral role for ERVK LTR repetitive elements.
2019-09-19 | GSE124212 | GEO
Project description:Background: Genomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on parent-of-origin, and is typically regulated by differential DNA methylation inherited from gametes. Imprinting is pervasive in murine extra-embryonic lineages and, uniquely, the imprinting of several genes has been found to be conferred non-canonically through maternally-inherited repressive histone modification H3K27me3. However, the underlying regulatory mechanisms of non-canonical imprinting in post-implantation development remain unexplored. Results: We identify imprinted regions in post-implantation epiblast and extra-embryonic ectoderm (ExE) by assaying allelic histone modifications (H3K4me3, H3K36me3, H3K27me3), gene expression and DNA methylation in reciprocal C57BL/6 and CAST hybrid embryos. We distinguish loci with DNA methylation- dependent (canonical) and independent (non-canonical) imprinting by assaying hybrid embryos with ablated maternally-inherited DNA methylation. We find that non-canonical imprints are localized to endogenous retrovirus-K (ERVK) long terminal repeats (LTRs), which act as imprinted promoters specifically in extra-embryonic lineages. Transcribed ERVK LTRs are CpG-rich and located in close proximity to gene promoters, and imprinting status is determined by their epigenetic patterning in the oocyte. Finally, we show that oocyte-derived H3K27me3 associates with non-canonical imprints is not maintained beyond pre-implantation development, and is replaced by secondary imprinted DNA methylation on the maternal allele in post-implantation ExE, while being completely silenced by bi-allelic DNA methylation in epiblast. Conclusions: This study reveals distinct epigenetic mechanisms regulating non-canonical imprinted gene expression between embryonic and extra-embryonic development, and identifies an integral role for ERVK LTR repetitive elements.
2019-09-19 | GSE124215 | GEO
Project description:Background: Genomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on parent-of-origin, and is typically regulated by differential DNA methylation inherited from gametes. Imprinting is pervasive in murine extra-embryonic lineages and, uniquely, the imprinting of several genes has been found to be conferred non-canonically through maternally-inherited repressive histone modification H3K27me3. However, the underlying regulatory mechanisms of non-canonical imprinting in post-implantation development remain unexplored. Results: We identify imprinted regions in post-implantation epiblast and extra-embryonic ectoderm (ExE) by assaying allelic histone modifications (H3K4me3, H3K36me3, H3K27me3), gene expression and DNA methylation in reciprocal C57BL/6 and CAST hybrid embryos. We distinguish loci with DNA methylation- dependent (canonical) and independent (non-canonical) imprinting by assaying hybrid embryos with ablated maternally-inherited DNA methylation. We find that non-canonical imprints are localized to endogenous retrovirus-K (ERVK) long terminal repeats (LTRs), which act as imprinted promoters specifically in extra-embryonic lineages. Transcribed ERVK LTRs are CpG-rich and located in close proximity to gene promoters, and imprinting status is determined by their epigenetic patterning in the oocyte. Finally, we show that oocyte-derived H3K27me3 associates with non-canonical imprints is not maintained beyond pre-implantation development, and is replaced by secondary imprinted DNA methylation on the maternal allele in post-implantation ExE, while being completely silenced by bi-allelic DNA methylation in epiblast. Conclusions: This study reveals distinct epigenetic mechanisms regulating non-canonical imprinted gene expression between embryonic and extra-embryonic development, and identifies an integral role for ERVK LTR repetitive elements.
2019-09-19 | GSE124213 | GEO
Project description:Cell size and the cell cycle are intrinsically coupled and abnormal increases in cell size are associated with senescence and permanent cell cycle arrest. The mechanism by which overgrowth primes cells to withdraw from the cell cycle remains unknown. We investigate this here using CDK4/6 inhibitors that arrest cell cycle progression during G0/G1 and are used in the clinic to treat ER+/HER2- metastatic breast cancer. We demonstrate that CDK4/6 inhibition promotes cellular overgrowth during G0/G1, causing p38MAPK-p53-p21-dependent cell cycle withdrawal. We find that cell cycle withdrawal is triggered by two waves of p21 induction. First, overgrowth during a long-term G0/G1 arrest induces an osmotic stress response. This stress response produces the first wave of p21 induction. Second, when CDK4/6 inhibitors are removed, a fraction of cells escape long term G0/G1 arrest and enter S-phase where overgrowth-driven replication stress results in a second wave of p21 induction that causes cell cycle withdrawal from G2, or the subsequent G1. We propose a model whereby both waves of p21 induction contribute to promote permanent cell cycle arrest. This model could explain why cellular hypertrophy is associated with senescence and why CDK4/6 inhibitors have long-lasting effects in patients.
2023-11-27 | PXD036519 | Pride