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Genetic stability and germ cell epigenetic instability in the Mtrr mouse model of transgenerational epigenetic inheritance.

ABSTRACT: Folate metabolism is important for DNA synthesis and repair through its role in the synthesis of the nucleotide thymidine. Mice with a hypomorphic mutation in the gene Mtrr have disrupted folate metabolism and show transgenerational inheritance of developmental abnormalities. We sought to explore if genetic mutations arising in the Mtrr mice may be responsible for the inheritance of these phenotypes. Therefore we sequenced the genomes of six embryos homozygous for the Mtrr mutation at embryonic day (E) 10.5 with developmental abnormalities. These were compared to two control C57Bl/6J embryos at E10.5, which had no developmental phenotypes. C57Bl/6J embryos were used as controls as they have the same genetic background as the mice with Mtrr mutation.

INSTRUMENT(S): HiSeq X Ten

ORGANISM(S): Mus musculus

SUBMITTER: Gina Blake

PROVIDER: E-MTAB-8513 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker.

Blake Georgina E T GET Zhao Xiaohui X Yung Hong Wa HW Burton Graham J GJ Ferguson-Smith Anne C AC Hamilton Russell S RS Watson Erica D ED

Nature communications 20210617 1

The mechanism behind transgenerational epigenetic inheritance is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrr hypomorphic mutation results in transgenerational epigenetic inheritance of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. Here, we use genome-wide approaches to reveal genetic stability in the Mtrr mod ...[more]

PMID: 34140513

Similar Datasets

Germ cell epigenetic instability in the Mtrr mouse model of transgenerational epigenetic inheritance

Project description:Folate metabolism is important for the generation of methyl groups required for cellular methylation reactions. Mice with a hypomorphic mutation in the gene Mtrr have disrupted folate metabolism and show transgenerational inheritance of developmental abnormalities. We sought to explore if DNA methylation patterns in the sperm of Mtrr mice may be disrupted. Therefore we performed MeDIP-seq on sperm collect from males with the Mtrr mutation (either heterozygous (Mtrr +/gt) or homozygous mutants (Mtrr gt/gt)), males ancestrally exposed to the Mtrr mutation (Mtrr +/+) and C57Bl/6J control males. C57Bl/6J males were used as controls as they have the same genetic background as the mice with Mtrr mutation.

2021-04-06 | E-MTAB-8533 | biostudies-arrayexpress

Placenta insufficiency caused by abnormal folate metabolism linked to fetal growth restriction across gestation and generations [RNA-Seq]

Project description:Folate is important for fetal development and growth, yet its role in placentation is understudied. Here we report that disrupting folate metabolism by the hypomorphic Mtrr mutation in mice causes morphological and functional defects in their placentas that correspond with early- and late-onset fetal growth restriction. Remarkably, Mtrr heterozygous males initiate inheritance of similar placenta phenotypes and fetal growth defects in their wildtype grandprogeny. An integrated genome-wide approach shows placental transcriptional change and epigenetic instability is caused by an intrinsic or ancestral Mtrr mutation, affecting genes important for placenta development and function (e.g., pregnancy specific glycoprotein (Psg)/Ceacams). Crucially, we establish a functional association between mouse placenta transcript levels and fetal size and identify a human PSG gene variant linked to birthweight. This study provides molecular insight into how folate metabolism influences placental development and attributes a potential multigenerational epigenetic mechanism to unexplained cases of fetal growth defects.

2023-06-06 | GSE233481 | GEO

Haploinsufficiency, but not defective paternal 5mC oxidation, accounts for the developmental defects of maternal Tet3 knockouts

Project description:DNA demethylation of paternal genome in zygotes takes place in various mammals including mice and human. Recent studies have revealed that this is achieved through Tet3-mediated iterative oxidation of 5-methylcytosine (5mC) coupled with replication-dependent dilution. Tet3-mediated paternal DNA demethylation is believed to be required for mouse development given that Tet3 heterozygous embryos, derived by fertilizing Tet3 knockout (KO) oocytes with wild-type (WT) sperms, exhibit 5mC oxidation defects and embryonic sublethality, Here we demonstrate that the sublethality phenotype of the maternal KO mice is caused by haploinsufficiency of Tet3, but not by defective paternal 5mC oxidation. We found that Tet3 heterozygous mice derived from crosses of heterozygous father or mother with WT mice also exhibit sublethality phenotype similarly to Tet3 maternal KO mice. Importantly, embryos reconstituted with WT paternal nuclei that bypassed 5mC oxidation develop to term and grow to adulthood normally. Genome-scale DNA methylation analysis of the maternal KO zygotes and blastocysts demonstrated that hypermethylation caused by the depletion of maternal Tet3 is largely diminished by the blastocyst stage. Our study thus not only demonstrates that Tet3-mediated paternal 5mC oxidation is dispensable for mouse development but also suggests the existence of a compensation mechanism in preimplantation embryos that can compensate for the defective 5mC oxidation in zygotes. This data set includes RRBS data of wild-type and maternal Tet3 KO zygotes and blastocysts (C57BL/6J x CAST/EiJ)

2015-02-28 | E-GEOD-62719 | biostudies-arrayexpress

Expression data from mouse intestine: C57Bl/6 MTHFR+/- vs BALB/c MTHFR+/-

2013-04-09 | GSE34010 | GEO

Dietary folate depletion and repletion

Project description:This SuperSeries is composed of the following subset Series: GSE9242: Dietary folate depletion and repletion in A/J and C57BL/6J mice GSE9243: Dietary folate depletion and repletion in C57BL/6J mice, ApoE knockout mice, and choline supplemented C57BL/6J mice Keywords: SuperSeries Refer to individual Series

2010-06-20 | E-GEOD-9245 | biostudies-arrayexpress

RNA-seq comparison of whole muscle between WT mice, dystrophic mice, and P2rx7-null dystrophic mice

Project description:Duchenne muscular dystrophy (DMD) is a debilitating and typically fatal X-linked progressive neuromuscular disorder that results in progressive muscle degeneration aggravated by sterile inflammation. The P2RX7 purinoceptor is an extracellular ATP-gated ion channel expressed in immune cells, and has been targeted in treatment of infectious and inflammatory diseases. In particular, P2xr7 receptor abnormalities have been demonstrated in mdx dystrophic mice, a model for DMD lacking expression of the full length dystrophin transcript through a single point mutation in exon 23. Here, we looked at the differential effects in gene expression regulation in whole muscle in dystrophic mdx mice with or without ablation of the P2rx7 purinoceptor.

2019-09-26 | E-MTAB-7698 | biostudies-arrayexpress

FolR1 gene ablation-induced changes in gene expression in mouse conotrucus tissue and developing heart

Project description:Defective function of FolR1 in mice results in inadequate transport, accumulation, or metabolism of folate during cardiovascular morphogenesis. We have observed cardiovascular abnormalities including outflow track defects and aortic arch artery defects in these genetically compromised mice. In order to investigate the mechanisms underlying the failure to complete cardiac development in the transgenic mouse model, we studied gene expression difference between FolR1 knockout embryos and normal embryos during outflow track septation (GD11:12, GSM78976 ... GSM78987), and studied gene expression difference between FolR1 knockout embryos and normal embryos during embryonic heart development(GD9:00 and GD10:00, GSM79024 ... GSM79035). Keywords: gene ablation response

2006-02-20 | GSE3487 | GEO

Expression data from mouse intestine: C57Bl/6 MTHFR+/- vs BALB/c MTHFR+/-

Project description:Previous studies in our laboratory have shown that low folate diet (control diet with 2mg folate/kg, low folate diet with 0.3mg folate/kg) can induce intestinal tumors in BALB/c mice. In addition, we reported that C57Bl/6J mice did not form tumors under the same conditions. We used microarrays to identify the genetic differences between BALB/c and C57Bl/6J mice that promote tumorigenesis in BALB/c mice. Two groups of mice will be used in the micro-array experiment. One group will consist of four BALB/c mice and the second group will consist of four C57Bl/6 mice. Both groups have mild MTHFR deficiency (Mthfr+/-) and will receive low folate diet (0.3 mg folate/kg) for one year. RNA samples will be extracted from duodenum, the first section of the small intestine where tumors were observed in BALB/c mice. Eight Affymetrix GeneChip Mouse Gene 1.0 ST Array Chips will be used in this experiment.

2013-04-09 | E-GEOD-34010 | biostudies-arrayexpress

Expression data from Neisseria gonorrhoeae (FA19)

Project description:Naturally occurring mtrR mutants of gonococci displaying clinically relevant levels of antibiotic resistance are often isolated from patients and mtrR mutants have been reported to be more fit than the wild type parent strain in a murine vaginal infection model. DNA-binding proteins, such as MtrR, that negatively regulate bacterial efflux pump genes have been considered to be “local” gene regulators, although there is increasing evidence that they can directly or indirectly influence expression of other genes. To define the regulatory properties of MtrR we employed microarray analysis of isogenic MtrR-positive and MtrR-negative gonococci. Keywords: single time point

2008-12-26 | GSE12686 | GEO

DNA methylation profiling of human naive embryonic stem cells

Project description:Human pluripotent cell lines were derived from blastocyst-stage embryos and propagated in self-renewal conditions that maintain features of naive pluripotency characteristic of mouse embryonic stem cells. Genome-wide DNA methylation status of HNES1 and HNES3 naive and primed cells was assessed with post-bisulfite adapter tagging (PBAT).

2016-03-01 | E-MTAB-4462 | biostudies-arrayexpress

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