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Partial Loss of Genomic Imprinting Reveals Important Roles for Kcnq1 and Peg10 Imprinted Domains in Placental Development.

Koppes E, Himes KP, Chaillet JR - PLoS ONE (2015)

Bottom Line: Methylation of some imprinted gDMDs, most notably Dlk1, was nearly normal in mid-gestation DNMT1o-deficient placentas, consistent with the notion that cells having lost methylation on these DMDs do not contribute significantly to placental development.First, loss of DNA methylation at the Peg10 imprinted gDMD associated with decreased embryonic viability and decreased labyrinthine volume.We conclude that the Peg10 and Kcnq1 ICRs are key regulators of mid-gestation placental function.

View Article: PubMed Central - PubMed

Affiliation: Magee-Womens Research Institute, Program in Integrative Molecular Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
Mutations in imprinted genes or their imprint control regions (ICRs) produce changes in imprinted gene expression and distinct abnormalities in placental structure, indicating the importance of genomic imprinting to placental development. We have recently shown that a very broad spectrum of placental abnormalities associated with altered imprinted gene expression occurs in the absence of the oocyte-derived DNMT1o cytosine methyltransferase, which normally maintains parent-specific imprinted methylation during preimplantation. The absence of DNMT1o partially reduces inherited imprinted methylation while retaining the genetic integrity of imprinted genes and their ICRs. Using this novel system, we undertook a broad and inclusive approach to identifying key ICRs involved in placental development by correlating loss of imprinted DNA methylation with abnormal placental phenotypes in a mid-gestation window (E12.5-E15.5). To these ends we measured DNA CpG methylation at 15 imprinted gametic differentially methylated domains (gDMDs) that overlap known ICRs using EpiTYPER-mass array technology, and linked these epigenetic measurements to histomorphological defects. Methylation of some imprinted gDMDs, most notably Dlk1, was nearly normal in mid-gestation DNMT1o-deficient placentas, consistent with the notion that cells having lost methylation on these DMDs do not contribute significantly to placental development. Most imprinted gDMDs however showed a wide range of methylation loss among DNMT1o-deficient placentas. Two striking associations were observed. First, loss of DNA methylation at the Peg10 imprinted gDMD associated with decreased embryonic viability and decreased labyrinthine volume. Second, loss of methylation at the Kcnq1 imprinted gDMD was strongly associated with trophoblast giant cell (TGC) expansion. We conclude that the Peg10 and Kcnq1 ICRs are key regulators of mid-gestation placental function.

No MeSH data available.


Related in: MedlinePlus

Hierarchical clustering of 24 E12.5 DNMT1o-deficient placentas based on gDMD methylation.Data is shown as the log2 transformed ratio of mt:wt gDMD methylation. The heat map displays normally methylated gDMDs as dark boxes whereas loss of methylation is indicated by lighter shades. The upper and side dendrograms display linkage between imprinted gDMDs and DNMT1o-deficient samples respectively. Imprinted gDMDs are labeled across the bottom axis. DNMT1o-deficient samples are labeled down the right hand side by cohort litter (Letters A-C) and conceptus (Numbers 1–8).
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pone.0135202.g002: Hierarchical clustering of 24 E12.5 DNMT1o-deficient placentas based on gDMD methylation.Data is shown as the log2 transformed ratio of mt:wt gDMD methylation. The heat map displays normally methylated gDMDs as dark boxes whereas loss of methylation is indicated by lighter shades. The upper and side dendrograms display linkage between imprinted gDMDs and DNMT1o-deficient samples respectively. Imprinted gDMDs are labeled across the bottom axis. DNMT1o-deficient samples are labeled down the right hand side by cohort litter (Letters A-C) and conceptus (Numbers 1–8).

Mentions: The spectrum of methylation among 12 gDMDs for each individual E12.5 DNMT1o-deficient placenta is displayed in the form of a heat map clustergram (Fig 2). Among the 24 E12.5 placentas represented in this manner, the majority of placentas have a unique gDMD methylation profile not found in other placentas, although there are a few cases of high similarity. For example placentas A8 and B2 have identical gDMD methylation profiles. Placentas A4 and B5 differ only at Grb10, Kcnq1 and H19 gDMDs, and placentas A3 and C1 are unique at only the Plagl1 gDMD. Clustering of the gDMDs at E12.5 indicate the genetically linked Peg10 and Mest gDMDs as well as the linked Kcnq1 and Snrpn gDMDs vary in conjunction. Although there is a trend toward more normal gDMD methylation levels at E15.5 and E17.5, each DNMT1o-deficient placenta at these stages still has a unique imprinted epigenotype (S3 and S4 Figs). These comparisons among placentas across the latter half of gestation point out the intrinsic power of the Dnmt1Δ1o maternal effect model to produce diverse and abnormal patterns of imprinted gDMD methylation.


Partial Loss of Genomic Imprinting Reveals Important Roles for Kcnq1 and Peg10 Imprinted Domains in Placental Development.

Koppes E, Himes KP, Chaillet JR - PLoS ONE (2015)

Hierarchical clustering of 24 E12.5 DNMT1o-deficient placentas based on gDMD methylation.Data is shown as the log2 transformed ratio of mt:wt gDMD methylation. The heat map displays normally methylated gDMDs as dark boxes whereas loss of methylation is indicated by lighter shades. The upper and side dendrograms display linkage between imprinted gDMDs and DNMT1o-deficient samples respectively. Imprinted gDMDs are labeled across the bottom axis. DNMT1o-deficient samples are labeled down the right hand side by cohort litter (Letters A-C) and conceptus (Numbers 1–8).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4524636&req=5

pone.0135202.g002: Hierarchical clustering of 24 E12.5 DNMT1o-deficient placentas based on gDMD methylation.Data is shown as the log2 transformed ratio of mt:wt gDMD methylation. The heat map displays normally methylated gDMDs as dark boxes whereas loss of methylation is indicated by lighter shades. The upper and side dendrograms display linkage between imprinted gDMDs and DNMT1o-deficient samples respectively. Imprinted gDMDs are labeled across the bottom axis. DNMT1o-deficient samples are labeled down the right hand side by cohort litter (Letters A-C) and conceptus (Numbers 1–8).
Mentions: The spectrum of methylation among 12 gDMDs for each individual E12.5 DNMT1o-deficient placenta is displayed in the form of a heat map clustergram (Fig 2). Among the 24 E12.5 placentas represented in this manner, the majority of placentas have a unique gDMD methylation profile not found in other placentas, although there are a few cases of high similarity. For example placentas A8 and B2 have identical gDMD methylation profiles. Placentas A4 and B5 differ only at Grb10, Kcnq1 and H19 gDMDs, and placentas A3 and C1 are unique at only the Plagl1 gDMD. Clustering of the gDMDs at E12.5 indicate the genetically linked Peg10 and Mest gDMDs as well as the linked Kcnq1 and Snrpn gDMDs vary in conjunction. Although there is a trend toward more normal gDMD methylation levels at E15.5 and E17.5, each DNMT1o-deficient placenta at these stages still has a unique imprinted epigenotype (S3 and S4 Figs). These comparisons among placentas across the latter half of gestation point out the intrinsic power of the Dnmt1Δ1o maternal effect model to produce diverse and abnormal patterns of imprinted gDMD methylation.

Bottom Line: Methylation of some imprinted gDMDs, most notably Dlk1, was nearly normal in mid-gestation DNMT1o-deficient placentas, consistent with the notion that cells having lost methylation on these DMDs do not contribute significantly to placental development.First, loss of DNA methylation at the Peg10 imprinted gDMD associated with decreased embryonic viability and decreased labyrinthine volume.We conclude that the Peg10 and Kcnq1 ICRs are key regulators of mid-gestation placental function.

View Article: PubMed Central - PubMed

Affiliation: Magee-Womens Research Institute, Program in Integrative Molecular Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
Mutations in imprinted genes or their imprint control regions (ICRs) produce changes in imprinted gene expression and distinct abnormalities in placental structure, indicating the importance of genomic imprinting to placental development. We have recently shown that a very broad spectrum of placental abnormalities associated with altered imprinted gene expression occurs in the absence of the oocyte-derived DNMT1o cytosine methyltransferase, which normally maintains parent-specific imprinted methylation during preimplantation. The absence of DNMT1o partially reduces inherited imprinted methylation while retaining the genetic integrity of imprinted genes and their ICRs. Using this novel system, we undertook a broad and inclusive approach to identifying key ICRs involved in placental development by correlating loss of imprinted DNA methylation with abnormal placental phenotypes in a mid-gestation window (E12.5-E15.5). To these ends we measured DNA CpG methylation at 15 imprinted gametic differentially methylated domains (gDMDs) that overlap known ICRs using EpiTYPER-mass array technology, and linked these epigenetic measurements to histomorphological defects. Methylation of some imprinted gDMDs, most notably Dlk1, was nearly normal in mid-gestation DNMT1o-deficient placentas, consistent with the notion that cells having lost methylation on these DMDs do not contribute significantly to placental development. Most imprinted gDMDs however showed a wide range of methylation loss among DNMT1o-deficient placentas. Two striking associations were observed. First, loss of DNA methylation at the Peg10 imprinted gDMD associated with decreased embryonic viability and decreased labyrinthine volume. Second, loss of methylation at the Kcnq1 imprinted gDMD was strongly associated with trophoblast giant cell (TGC) expansion. We conclude that the Peg10 and Kcnq1 ICRs are key regulators of mid-gestation placental function.

No MeSH data available.


Related in: MedlinePlus