Allele and dosage specificity of the Peg3 imprinted domain

Bretz, Corey L.; Frey, Wesley D.; Teruyama, Ryoichi; Kim, Joomyeong

doi:10.1371/journal.pone.0197069

Cited by 9 publications

(15 citation statements)

References 34 publications

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“…In a prior mutant model of Peg3 , reduced numbers of Oxt-expressing neurons were initially observed, which was then thought to be a main cause for the milk provision problem [ 9 ]. However, this has been later argued by two independent studies reporting that the mutations did not cause any change in the numbers of Oxt-immunoreactive neurons in the hypothalamus [ 13 , 16 , 17 ]. Nevertheless, subsequent experiments confirmed again the presence of the milk provision problem in several Peg3-KO models, and further substantiated that this defect was more pronounced through the conditional mutation of Peg3 in the mammary gland than in the hypothalamus [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Oxytocin receptor is regulated by Peg3

et al. 2018

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Mouse Peg3 encodes a DNA-binding protein involved in the milk letdown process. In the current study, we tested whether PEG3 controls the expression of the oxytocin receptor gene. According to the results, PEG3 directly binds to a genomic region within the 3rd exon of Oxtr, which contains a DNA-binding motif for PEG3. In nursing female mice, removal of PEG3 resulted in the increased expression of Oxtr in mammary epithelial cells and also in the hypothalamus. This suggests a repressor role of PEG3 in the expression of Oxtr in these tissues. Overall, this study suggests that Peg3 may function as a direct transcriptional regulator for Oxtr expression that acts to moderate the milk letdown process.

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Section: Introductionmentioning

confidence: 99%

Oxytocin receptor is regulated by Peg3

et al. 2018

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“…The expression levels of Zim1 were 2.0-fold up-regulated in KO2/WT relative to those from WT/WT. We have previously reported that paternal deletion of the Peg3-DMR usually causes paternal activation and subsequent bi-allelic expression of Zim1 [ 17 , 22 ]. Thus, the observed 2.0-fold up-regulation may reflect the combined contribution from both alleles with each being equally 1.0-fold [ 17 , 22 ].…”

Section: Resultsmentioning

confidence: 99%

“…We have previously reported that paternal deletion of the Peg3-DMR usually causes paternal activation and subsequent bi-allelic expression of Zim1 [ 17 , 22 ]. Thus, the observed 2.0-fold up-regulation may reflect the combined contribution from both alleles with each being equally 1.0-fold [ 17 , 22 ]. This further indicated that the expression levels of the maternal allele of Zim 1 were not affected in response to the paternal deletion of the Peg3 -DMR.…”

Section: Resultsmentioning

confidence: 99%

Trans-allelic mutational effects at the Peg3 imprinted locus

Bretz

Kim

2018

PLoS ONE

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How one allele interacts with the other for the function of a gene is not well understood. In this study, we tested potential allelic interaction at the Peg3 imprinted locus with several mutant alleles targeting an Imprinting Control Region, the Peg3-DMR. According to the results, maternal deletion of the Peg3-DMR resulted in 2-fold up-regulation of two paternally expressed genes, Peg3 and Usp29. These trans-allelic mutational effects were observed consistently throughout various tissues with different developmental stages. These effects were also associated mainly with the genetic manipulation of the Peg3-DMR, but not with the other genomic changes within the Peg3 locus. The observed trans-allelic effects were unidirectional with the maternal influencing the paternal allele, but not with the opposite direction. Overall, the observed mutational effects suggest the presence of previously unrecognized trans-allelic regulation associated with the Peg3-DMR.

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“…We hypothesize that GADD45 may play a direct role in demethylating anti-angiogenic and proautophagic gene promoters. Especially important are genes that are known to be controlled by differential methylation including paternally expressed gene 3 (Peg3) which is differentially methylated in paternal and maternal alleles (63). Notably, we have discovered that Peg3 is a master regulator of autophagy (64) and is markedly induced at both the mRNA and protein level in endothelial cells exposed to endorepellin (45).…”

Section: Endorepellin-activated Stress Axis Inhibits Angiogenesismentioning

confidence: 99%

Endorepellin evokes an angiostatic stress signaling cascade in endothelial cells

Kapoor

Chen²,

Iozzo

2020

Journal of Biological Chemistry

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Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan perlecan, influences various signaling pathways in endothelial cells by binding to VEGFR2. In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4, and GADD45α. Specifically, endorepellin evoked transient activation of VEGFR2, which, in turn, phosphorylated PERK at Thr980. Subsequently, PERK phosphorylated eIF2α at Ser51, upregulating its downstream effector proteins ATF4 and GADD45α. RNAi-mediated knockdown of PERK or eIF2α abrogated the endorepellin-mediated up-regulation of GADD45α, the ultimate effector protein of this stress signaling cascade. To functionally validate these findings, we utilized an ex vivo model of angiogenesis. Exposure of the aortic rings embedded in 3D fibrillar collagen to recombinant endorepellin for 2–4 h activated PERK and induced GADD45α vis à vis vehicle-treated counterparts. Similar effects were obtained with the established cellular stress inducer tunicamycin. Notably, chronic exposure of aortic rings to endorepellin for 7–9 days markedly suppressed vessel sprouting, an angiostatic effect that was rescued by blocking PERK kinase activity. Our findings unravel a mechanism by which an extracellular matrix protein evokes stress signaling in endothelial cells, which leads to angiostasis.

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Allele and dosage specificity of the Peg3 imprinted domain

Cited by 9 publications

References 34 publications

Oxytocin receptor is regulated by Peg3

Oxytocin receptor is regulated by Peg3

Trans-allelic mutational effects at the Peg3 imprinted locus

Endorepellin evokes an angiostatic stress signaling cascade in endothelial cells

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