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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Maternal DNA methylation regulates early trophoblast development

ABSTRACT: Critical roles for DNA methylation in embryonic development are well established, but less is known about the roles of DNA methylation during trophoblast development, the extraembryonic lineage that gives rise to the placenta. Here we dissected the role of DNA methylation in trophoblast development by performing mRNA and DNA methylation profiling of Dnmt3a/3b-null trophoblast. We find that most gene deregulation is explained by an erasure of maternal methylation in the oocyte, but partially independent of loss of imprinting of the trophoblast-essential Ascl2 gene. Our results reveal that maternal DNA methylation controls multiple differentiation and physiological processes in trophoblast via both imprinting-dependent and -independent mechanisms. mRNA-seq and WGBS-seq of maternal Dnmt3a/3b-null trophoblast; mRNA-seq of maternal Ascl2 KO trophoblast

ORGANISM(S): Mus musculus

SUBMITTER: Felix Krueger

PROVIDER: E-GEOD-66049 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Maternal DNA methylation regulates early trophoblast development

Project description:Critical roles for DNA methylation in embryonic development are well established, but less is known about the roles of DNA methylation during trophoblast development, the extraembryonic lineage that gives rise to the placenta. Here we dissected the role of DNA methylation in trophoblast development by performing mRNA and DNA methylation profiling of Dnmt3a/3b-null trophoblast. We find that most gene deregulation is explained by an erasure of maternal methylation in the oocyte, but partially independent of loss of imprinting of the trophoblast-essential Ascl2 gene. Our results reveal that maternal DNA methylation controls multiple differentiation and physiological processes in trophoblast via both imprinting-dependent and -independent mechanisms.

2016-01-07 | GSE66049 | GEO

Disabling de novo DNA methylation in embryonic stem cells allows an illegitimate fate trajectory

Project description:Genome remethylation is essential for mammalian development but specific reasons are unclear. Here we examined embryonic stem (ES) cell fate in the absence of de novo DNA methyltransferases. We observed that ES cells deficient for both Dnmt3a and Dnmt3b are rapidly eliminated from chimeras. On further investigation we found that in vivo and in vitro the formative pluripotency transition is derailed toward production of trophoblast. This aberrant trajectory is associated with failure to suppress activation of Ascl2. Ascl2 encodes a bHLH transcription factor expressed in the placenta. Misexpression of Ascl2 in ES cells provokes transdifferentiation to trophoblast-like cells. Conversely, Ascl2 deletion rescues formative transition of Dnmt3a/b mutants and improves contribution to chimeric epiblast. Thus, de novo DNA methylation safeguards against ectopic activation of Ascl2. However, Dnmt3a/b-deficient cells remain defective in ongoing embryogenesis. We surmise that multiple developmental transitions may be secured by DNA methylation silencing potentially disruptive genes. This SuperSeries is composed of the SubSeries listed below.

2021-08-31 | GSE158347 | GEO

De novo DNA methylation suppresses aberrant fate trajectory during epiblast transition [ATAC-seq]

Project description:Genome remethylation is essential for mammalian development. Here we examined cell fate in the absence of de novo DNA methyltransferases. We found that embryonic stem (ES) cells deficient for Dnmt3a and Dnmt3b are rapidly eliminated from chimaeras. Pluripotency progression is derailed towards extra-embryonic trophoblast. This aberrant trajectory is propelled by failure to methylate and suppress expression of Ascl2 during formative transition. Ascl2 deletion rescues transition and improves contribution to chimaeric epiblast but mutant cells are progressively lost in later development. These findings indicate that methylation constrains transcriptome trajectories during developmental transitions by silencing potentially disruptive genes. This submission is ATAC-seq.

2021-09-01 | GSE158344 | GEO

De novo DNA methylation suppresses aberrant fate trajectory during epiblast transition [RNA-seq]

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Mechanisms and function of de novo DNA methylation in placental development [ChIP-seq]

Project description:DNA methylation is a repressive epigenetic modification that is essential for development, exemplified by the embryonic and perinatal lethality observed in mice lacking de novo DNA methyltransferases (DNMTs). Here we characterise the role for DNMT3A, 3B and 3L in gene regulation and development of the mouse placenta. We demonstrate that each of the DNMTs is required to establish the placental methylome and is distinctly targeted to genome based on underlying chromatin features. Loss of Dnmt3b results in de-repression of germline genes in trophoblast lineages and impaired development of the placental maternal-foetal interface. Critically, loss of DNA methylation in the placenta did not lead to abnormalities in lineage specification or cell identity, but to defective formation and vascularisation of the placental labyrinth. Using Sox2-Cre to delete Dnmt3b in the embryo, leaving expression intact in placental trophoblast cells, we were able to rescue the placental phenotype and, consequently, the embryonic lethality, as Dnmt3b null embryos could now survive to birth. We conclude that the principal function of DNA methylation during embryogenesis is to regulate placental function, which in turn is critical for embryo survival.

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Mechanisms and function of de novo DNA methylation in placental development [PBAT]

2022-12-15 | GSE203292 | GEO

Mechanisms and function of de novo DNA methylation in placental development [RNA-Seq]

2022-12-15 | GSE203291 | GEO

Mechanisms and function of de novo DNA methylation in placental development [snRNA-seq]

2022-12-15 | GSE203226 | GEO

Dnmt3a and Dnmt3b-mediated decommissioning of fetal enhancers linked to kidney disease

Project description:Cytosine methylation is an epigenetic mark that dictates cell fate and response to stimuli. The timing and establishment of methylation logic during kidney development remains unknown. DNA methyltransferase 3a and 3b are the enzymes capable of establishing de novo methylation. We generated mice with genetic deletion of Dnmt3a and Dnmt3b in nephron progenitor cells (Six2Cre Dnmt3a/3b) and kidney tubule cells (KspCre Dnmt3a/3b). We characterized KspCre Dnmt3a/3b mice at baseline and after injury. Unbiased omics profiling, such as whole genome bisulfite sequencing, reduced representation bisulfite sequencing and RNA sequencing were performed on whole-kidney samples and isolated renal tubule cells. KspCre Dnmt3a/3b mice showed no obvious morphologic and functional alterations at baseline. Knockout animals exhibited increased resistance to cisplatin-induced kidney injury, but not to folic acid–induced fibrosis. Whole-genome bisulfite sequencing indicated that Dnmt3a and Dnmt3b play an important role in methylation of gene regulatory regions that act as fetal-specific enhancers in the developing kidney but are decommissioned in the mature kidney. Loss of Dnmt3a and Dnmt3b resulted in failure to silence developmental genes. We also found that fetal-enhancer regions methylated by Dnmt3a and Dnmt3b were enriched for kidney disease genetic risk loci. Methylation patterns of kidneys from patients with CKD showed defects similar to those in mice with Dnmt3a and Dnmt3b deletion. Our results indicate a potential locus-specific convergence of genetic, epigenetic, and developmental elements in kidney disease development.

2020-03-03 | GSE134267 | GEO

Reduced representative bisulfite sequencing (RRBS) analysis for a genome-wide comparison of DNA methylation in wild-type, USP7-KO-1, DNMT3A/3B-DKO and DNMT3A/DNMT3B/USP7-TKO HeLa cell lines.

Project description:To better characterize the effects of USP7 on DNA methylation, we performed reduced representative bisulfite sequencing (RRBS) analysis for a genome-wide comparison of DNA methylation in wild-type, USP7-KO-1, DNMT3A/3B-DKO and DNMT3A/DNMT3B/USP7-TKO HeLa cell lines. RRBS analysis showed increased DNA methylation in USK7-KO cells and loss of USP7 elevates DNA methylation on pre-existing sites and de novo methylation.

2020-09-07 | GSE136159 | GEO

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