Placental expression of imprinted genes varies with sampling site and mode of delivery

Janssen, Anna B.; Tunster, Simon James; Savory, N.A.; Holmes, Amey; Beasley, John E.; Parveen, Sajitha; Penketh, Richard; Roshan, John

doi:10.1016/j.placenta.2015.06.011

Cited by 28 publications

(17 citation statements)

References 53 publications

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“…The samples used in this study were heterogenous with respect to several parameters known to affect placental gene expression including: delivery mode (30), sex (31), and pregnancy complications (32, 33) (Supplemental…”

Section: Discussionmentioning

confidence: 99%

Effects of RNA integrity on transcript quantification by total RNA sequencing of clinically collected human placental samples

Reiman¹,

Laan

Rull

et al. 2017

FASEB j.

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RNA degradation is a ubiquitous process that occurs in living and dead cells, as well as during handling and storage of extracted RNA. Reduced RNA quality caused by degradation is an established source of uncertainty for all RNA-based gene expression quantification techniques. RNA sequencing is an increasingly preferred method for transcriptome analyses, and dependence of its results on input RNA integrity is of significant practical importance. This study aimed to characterize the effects of varying input RNA integrity [estimated as RNA integrity number (RIN)] on transcript level estimates and delineate the characteristic differences between transcripts that differ in degradation rate. The study used ribodepleted total RNA sequencing data from a real-life clinically collected set (n = 32) of human solid tissue (placenta) samples. RIN-dependent alterations in gene expression profiles were quantified by using DESeq2 software. Our results indicate that small differences in RNA integrity affect gene expression quantification by introducing a moderate and pervasive bias in expression level estimates that significantly affected 8.1% of studied genes. The rapidly degrading transcript pool was enriched in pseudogenes, short noncoding RNAs, and transcripts with extended 39 untranslated regions. Typical slowly degrading transcripts (median length, 2389 nt) represented protein coding genes with 4-10 exons and high guanine-cytosine content.-Reiman, M., Laan, M., Rull, K., Sõber, S. Effects of RNA integrity on transcript quantification by total RNA sequencing of clinically collected human placental samples. FASEB J. 31, 3298-3308 (2017). www.fasebj.orgRNA degradation is an intrinsic part of cellular metabolism and gene expression regulation (1) that continues after cell death. It occurs in ante-and postmortem tissues, as well as in extracted RNA during storage and handling. It is a known confounder for all RNA-based gene expression quantification methods, including Northern blot (2), quantitative RT-PCR (3), expression microarrays (4), and RNA sequencing (5, 6). Considerable effort is routinely devoted to ensuring maximum practicable RNA quality before conducting such studies. RNA sequencing (RNA-Seq) is gaining dominance as a method of choice for transcriptome-wide gene expression quantification because of its wide applicability, sensitivity, and increasing availability (7). At present, there is no consensus on the extent of RNA-quality-dependent confounding and what methods should be applied to get accurate differential expression estimates (5, 8) from RNA sequencing (RNA-Seq) data. The primary method to mitigate it is to select a tissue-, organism-, and quantification platform-specific RNA integrity cutoff and to assume that RNA degradation does not have a noticeable effect on samples above this threshold. In many cases, however, practical limitations preclude the possibility of obtaining RNA of pristine quality. Such cases may include samples collected in clinical settings, postmortem or legacy samples, and ot...

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Section: Discussionmentioning

confidence: 99%

Effects of RNA integrity on transcript quantification by total RNA sequencing of clinically collected human placental samples

Reiman¹,

Laan

Rull

et al. 2017

FASEB j.

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“…Imprinted gene expression in the placenta can be influenced by many factors including differences in the sampling site, mode of delivery ( Janssen et al, 2015 ), fetal sex ( Iglesias-Platas et al, 2014 ), and gestational age ( Demetriou et al, 2014 ). Regional variation in the expression of PHLDA2 has previously been reported with modest elevation of expression in samples taken at the distal edge of the placenta compared to the ones near the cord insertion site ( Janssen et al, 2015 ) which may partially be attributed to differences in placental architecture and blood supply. To overcome this we routinely obtained biopsies from the same location on the fetal side of the placenta within 2 cm of the cord insertion.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Characterization of CDKN1C in Placenta Samples from Non-syndromic Intrauterine Growth Restriction

2016

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The cyclin-dependent kinase (CDK)-inhibitor 1C (CDKN1C) gene is expressed from the maternal allele and is located within the centromeric imprinted domain at chromosome 11p15. It is a negative regulator of proliferation, with loss-of-function mutations associated with the overgrowth disorder Beckwith–Wiedemann syndrome. Recently, gain-of-function mutations within the PCNA domain have been described in two disorders characterized by growth failure, namely IMAGe (intra-uterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital abnormalities) syndrome and Silver–Russell syndrome (SRS). Over-expression of CDKN1C by maternally inherited microduplications also results in SRS, suggesting that in addition to activating mutations this gene may regulate growth by changes in dosage. To determine if CDKN1C is involved in non-syndromic IUGR we compared the expression and DNA methylation levels in a large cohort of placental biopsies from IUGR and uneventful pregnancies. We observe higher levels of expression of CDKN1C in IUGR placentas compared to those of controls. All placenta biopsies heterozygous for the PAPA repeat sequence in exon 2 showed appropriate monoallelic expression and no mutations in the PCNA domain were observed. The expression profile was independent of both genetic or methylation variation in the minimal CDKN1C promoter interval and of methylation of the cis-acting maternally methylated region associated with the neighboring KCNQ1OT1 non-coding RNA. Chromatin immunoprecipitation revealed binding sites for CTCF within the unmethylated CDKN1C gene body CpG island and putative enhancer regions, associated with the canonical enhancer histone signature, H3K4me1 and H3K27ac, located ∼58 and 360 kb away. Using 3C-PCR we identify constitutive higher-order chromatin loops that occur between one of these putative enhancer regions and CDKN1C in human placenta tissues, which we propose facilitates expression.

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“…For example, the maternally expressed imprinted gene CYCLIN-DEPENDENT KINASE INHIBITOR 1C ( CDKN1C ) has variously been reported to be significantly decreased [97], increased [98, 99], or unaltered [100] in preeclamptic placentas. These conflicting results may be explained by a difference in mode of delivery, given recent evidence demonstrating significantly increased CDKN1C expression in laboring versus non-laboring placentas [101]. Some mothers carrying babies with loss-of-function of CDKN1C have a very severe form of preeclampsia called HELLP (Hemolysis, Elevated Liver enzymes, Low platelet count) syndrome which is a life-threatening complication [102].…”

Section: Methodsmentioning

confidence: 99%

Neurodevelopmental consequences in offspring of mothers with preeclampsia during pregnancy: underlying biological mechanism via imprinting genes

Nomura

Roshan

Janssen

et al. 2017

Arch Gynecol Obstet

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Purpose Preeclampsia is known to be a leading cause of mortality and morbidity among mothers and their infants. Approximately 3–8% of all pregnancies in the US are complicated by preeclampsia and another 5–7% by hypertensive symptoms. However, less is known about its long-term influence on infant neurobehavioral development. The current review attempts to demonstrate new evidence for imprinting gene dysregulation caused by hypertension, which may explain the link between maternal preeclampsia and neurocognitive dysregulation in offspring. Method Pub Med and Web of Science databases were searched using the terms “preeclampsia,” “gestational hypertension,” “imprinting genes,” “imprinting dysregulation,” and “epigenetic modification,” in order to review the evidence demonstrating associations between preeclampsia and suboptimal child neurodevelopment, and suggest dysregulation of placental genomic imprinting as a potential underlying mechanism. Results The high mortality and morbidity among mothers and fetuses due to preeclampsia is well known, but there is little research on the long-term biological consequences of preeclampsia and resulting hypoxia on the fetal/child neurodevelopment. In the past decade, accumulating evidence from studies that transcend disciplinary boundaries have begun to show that imprinted genes expressed in the placenta might hold clues for a link between preeclampsia and impaired cognitive neurodevelopment. A sudden onset of maternal hypertension detected by the placenta may result in misguided biological programming of the fetus via changes in the epigenome, resulting in suboptimal infant development. Conclusion Furthering our understanding of the molecular and cellular mechanisms through which neurodevelopmental trajectories of the fetus/infant are affected by preeclampsia and hypertension will represent an important first step toward preventing adverse neurodevelopment in infants.

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Placental expression of imprinted genes varies with sampling site and mode of delivery

Cited by 28 publications

References 53 publications

Effects of RNA integrity on transcript quantification by total RNA sequencing of clinically collected human placental samples

Effects of RNA integrity on transcript quantification by total RNA sequencing of clinically collected human placental samples

Epigenetic Characterization of CDKN1C in Placenta Samples from Non-syndromic Intrauterine Growth Restriction

Neurodevelopmental consequences in offspring of mothers with preeclampsia during pregnancy: underlying biological mechanism via imprinting genes

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