Dataset Information

Compromised global embryonic transcriptome associated with advanced maternal age.

ABSTRACT:

Purpose

To investigate the global transcriptome and associated embryonic molecular networks impacted with advanced maternal age (AMA).

Methods

Blastocysts derived from donor oocyte IVF cycles with no male factor infertility (< 30 years of age) and AMA blastocysts (≥ 42 years) with no other significant female factor infertility or male factor infertility were collected with informed patient consent. RNA sequencing libraries were prepared using the SMARTer® Ultra® Low Kit (Clontech Laboratories) and sequenced on the Illumina HiSEQ 4000. Bioinformatics included Ingenuity® Pathway Analysis (Qiagen) with ViiA™ 7 qPCR utilized for gene expression validation (Applied Biosystems).

Results

A total of 2688 significant differentially expressed transcripts were identified to distinguish the AMA blastocysts from young, donor controls. 2551 (95%) of these displayed decreased transcription in the blastocysts from older women. Pathway analysis revealed three altered molecular signaling networks known to be critical for embryo and fetal development: CREBBP, ESR1, and SP1. Validation of genes within these networks confirmed the global decreased transcription observed in AMA blastocysts (P < 0.05).

Conclusions

A significant, overall decreased global transcriptome was observed in blastocysts from AMA women. The ESR1/SP1/CREBBP pathway, in particular, was found to be a highly significant upstream regulator impacting biological processes that are vital during embryonic patterning and pre-implantation development. These results provide evidence that AMA embryos are compromised on a cell signaling level which can repress the embryo's ability to proliferate and implant, contributing to a deterioration of reproductive outcomes.

SUBMITTER: McCallie BR

PROVIDER: S-EPMC6541584 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Compromised global embryonic transcriptome associated with advanced maternal age.

McCallie Blair R BR Parks Jason C JC Trahan G Devon GD Jones Kenneth L KL Coate Breanne D BD Griffin Darren K DK Schoolcraft William B WB Katz-Jaffe Mandy G MG

Journal of assisted reproduction and genetics 20190425 5

<h4>Purpose</h4>To investigate the global transcriptome and associated embryonic molecular networks impacted with advanced maternal age (AMA).<h4>Methods</h4>Blastocysts derived from donor oocyte IVF cycles with no male factor infertility (< 30 years of age) and AMA blastocysts (≥ 42 years) with no other significant female factor infertility or male factor infertility were collected with informed patient consent. RNA sequencing libraries were prepared using the SMARTer® Ultra® Low Kit (Clontech ...[more]

PMID: 31025158

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Project description:BackgroundMaternal hypertensive disorders (MHD) are leading causes of maternal morbidity and mortality worldwide, particularly among reproductive-age women of advanced maternal age (AMA), representing a significant global public health challenge.ObjectiveThis study aimed to analyze the global trends, inequalities, and disparities in the burden of MHD among reproductive-age AMA women from 1990 to 2021.MethodsWe conducted a population-based study using data from the Global Burden of Disease (GBD) 2021 study, covering 204 countries and territories. The study included women aged 35-49 years with hypertensive disorders during pregnancy. We assessed age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR) of MHD among reproductive-age AMA women. Temporal trends were evaluated using joinpoint regression analysis, while health inequalities were measured using the concentration index and the slope index of inequality (SII).ResultsBetween 1990 and 2021, the global ASIR of MHD decreased from 568.10 (95% UI: 412.06-738.55) to 491.49 (95% UI: 368.78-619.84) per 100,000 population (AAPC: -0.46%, 95% CI: -0.54% to -0.38%), and ASDR declined from 2.57 (95% UI: 2.23-2.97) to 1.44 (95% UI: 1.19-1.76) per 100,000 population (AAPC: -1.83%, 95% CI: -1.99% to -1.67%). Substantial disparities persisted across socio-demographic index (SDI) regions, with high and high-middle SDI regions showing increasing incidence trends (AAPC: 2.36% and 1.45%, respectively). The slope index of inequality (SII) for ASIR improved from -3,052.73 (95% CI: -3,329.55 to -2,775.91) to -1,209.36 (95% CI: -1,393.12 to -1,025.61) per 100,000 women, while the SII for ASDR decreased from -11.29 (95% CI: -12.38 to -10.20) to -3.66 (95% CI: -4.13 to -3.20) deaths per 100,000 women. The concentration index for ASIR showed slight improvement (from -0.46 to -0.34), while ASDR inequality marginally worsened (from -0.62 to -0.66).ConclusionDespite overall declines in MHD burden, significant disparities persist, particularly in low SDI regions. These findings highlight the need for targeted public health interventions to reduce inequalities, improve healthcare access, and enhance maternal outcomes for reproductive-age AMA women globally.

Project description:BackgroundThe number of women delivering at advanced maternal age (AMA; > = 35) continuously increases in developed and high-income countries. Large cohort studies have associated AMA with increased risks of various pregnancy complications and adverse pregnancy outcomes, which raises great concerns about the adverse effect of AMA on the long-term health of offspring. Specific acquired characteristics of parents can be passed on to descendants through certain molecular mechanisms, yet the underlying connection between AMA-related alterations in parents and that in offspring remains largely uncharted.MethodsWe profiled the DNA methylomes of paired parental peripheral bloods and cord bloods from 20 nuclear families, including 10 AMA and 10 Young, and additional transcriptomes of 10 paired maternal peripheral bloods and cord bloods.ResultsWe revealed that AMA induced aging-like changes in DNA methylome and gene expression in both parents and offspring. The expression changes in several genes, such as SLC28A3, were highly relevant to the disorder in DNA methylation. In addition, AMA-related differentially methylated regions (DMRs) identified in mother and offspring groups showed remarkable similarities in both genomic locations and biological functions, mainly involving neuron differentiation, metabolism, and histone modification pathways. AMA-related differentially expressed genes (DEGs) shared by mother and offspring groups were highly enriched in the processes of immune cell activation and mitotic nuclear division. We further uncovered developmental-dependent dynamics for the DNA methylation of intergenerationally correlated DMRs during pre-implantation embryonic development, as well as diverse gene expression patterns during gametogenesis and early embryonic development for those common AMA-related DEGs presenting intergenerational correlation, such as CD24. Moreover, some intergenerational DEGs, typified by HTRA3, also showed the same significant alterations in AMA MII oocyte or blastocyst.ConclusionsOur results reveal potential intergenerational inheritance of both AMA-related DNA methylome and transcriptome and provide new insights to understand health problems in AMA offspring.

Project description:The effects of advanced maternal age (AMA) on the neurodevelopment of offspring are becoming increasingly important. Myelination is an important aspect of brain development; however, a limited number of studies have focused on the effects of AMA on myelination in offspring. The current study aims to evaluate the association between AMA and myelin sheath development in offspring. We studied the learning and memory function of immature offspring using the novel object recognition test. Then, we investigated the expression of myelin basic protein (MBP) in the immature offspring of young (3-month-old) and old (12-month-old) female rats at different time points (14, 28, and 60 days) after birth with immunofluorescence and western blotting. The myelin sheath ultrastructure was observed with transmission electron microscopy in immature and mature offspring. Extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2) were investigated by western blot in immature offspring at the above time points. AMA impaired the memory function of offspring during early postnatal days. The MBP expression level gradually increased with postnatal development in the offspring of both the AMA and Control (Ctl) groups, but the MBP level in the offspring of the AMA group was lower than that of the Ctl group at 14 days after birth. In addition, the ultrastructure of the myelin sheath was defective in AMA offspring during the early postnatal period; however, the myelin sheath was not significantly affected in offspring during adulthood. Interestingly, ERK phosphorylation at 14 days after birth was lower in AMA offspring than in Ctl offspring. However, ERK phosphorylation at 28 days after birth was higher in AMA offspring than in Ctl offspring. The peak of ERK phosphorylation in the AMA group was abnormal and delayed. Our results indicated that AMA is associated with poor developmental myelin formation in offspring. The ERK signaling pathway may play an essential role in the adverse effects of AMA on the offspring myelin sheath development.

Project description:BackgroundCharacterization of gene expression signatures for cardiomyocytes derived from embryonic stem cells will help to define their early biologic processes.ResultsA transgenic alpha-myosin heavy chain (MHC) embryonic stem cell lineage was generated, exhibiting puromycin resistance and expressing enhanced green fluorescent protein (EGFP) under the control of the alpha-MHC promoter. A puromycin-resistant, EGFP-positive, alpha-MHC-positive cardiomyocyte population was isolated with over 92% purity. RNA was isolated after electrophysiological characterization of the cardiomyocytes. Comprehensive transcriptome analysis of alpha-MHC-positive cardiomyocytes in comparison with undifferentiated alpha-MHC embryonic stem cells and the control population from 15-day-old embryoid bodies led to identification of 884 upregulated probe sets and 951 downregulated probe sets in alpha-MHC-positive cardiomyocytes. A subset of upregulated genes encodes cytoskeletal and voltage-dependent channel proteins, and proteins that participate in aerobic energy metabolism. Interestingly, mitosis, apoptosis, and Wnt signaling-associated genes were downregulated in the cardiomyocytes. In contrast, annotations for genes upregulated in the alpha-MHC-positive cardiomyocytes are enriched for the following Gene Ontology (GO) categories: enzyme-linked receptor protein signaling pathway (GO:0007167), protein kinase activity (GO:0004672), negative regulation of Wnt receptor signaling pathway (GO:0030178), and regulation of cell size (O:0008361). They were also enriched for the Biocarta p38 mitogen-activated protein kinase signaling pathway and Kyoto Encyclopedia of Genes and Genomes (KEGG) calcium signaling pathway.ConclusionThe specific pattern of gene expression in the cardiomyocytes derived from embryonic stem cells reflects the biologic, physiologic, and functional processes that take place in mature cardiomyocytes. Identification of cardiomyocyte-specific gene expression patterns and signaling pathways will contribute toward elucidating their roles in intact cardiac function.

Project description:Objective: Adverse pregnancy outcomes are closely related to advanced maternal age (AMA; age at pregnancy ≥35 years). Little research has been reported on aneuploid abnormalities and pathogenic copy number variations (CNVs) affecting pregnancy outcomes in women with AMA. The purpose of this study was to assess CNVs associated with AMA in prenatal diagnosis to determine the characteristics of pathogenic CNVs and assist with genetic counseling of women with AMA. Methods: Among 277 fetuses of women with AMA, 218 (78.7%) were isolated AMA fetuses and 59 (21.3%) were non-isolated AMA fetuses and showed ultrasound anomalies from January 2021 to October 2022. Isolated AMA was defined as AMA cases without sonographic abnormalities. Non-isolated AMA was defined as AMA cases with sonographic abnormalities such as sonographic soft markers, widening of the lateral ventricles, or extracardiac structural anomalies. The amniotic fluid cells underwent routine karyotyping followed by single nucleotide polymorphism array (SNP-array) analysis. Results: Of the 277 AMA cases, karyotype analysis identified 20 chromosomal abnormalities. As well as 12 cases of chromosomal abnormalities corresponded to routine karyotyping, the SNP array identified an additional 14 cases of CNVs with normal karyotyping results. There were five pathogenetic CNVs, seven variations of uncertain clinical significance (VOUS), and two benign CNVs. The detection rate of abnormal CNVs in non-isolated AMA cases was increasing (13/59; 22%) than in isolated AMA cases (13/218; 5.96%) (p < 0.001). We also determined that pathogenic CNVs affected the rate of pregnancy termination in women with AMA. Conclusion: Aneuploid abnormalities and pathogenic CNVs affect pregnancy outcomes in women with AMA. SNP array had a higher detection rate of genetic variation than did karyotyping and is an important supplement to karyotype analysis, which enables better informed clinical consultation and clinical decision-making.

Dataset Information

Compromised global embryonic transcriptome associated with advanced maternal age.

Purpose

Methods

Results

Conclusions

Publications

Compromised global embryonic transcriptome associated with advanced maternal age.

Similar Datasets

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