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Journal of Assisted Reproduction and Genetics
Published in: Journal of Assisted Reproduction and Genetics 5/2019

Open Access 01-05-2019 | Embryo Biology

Compromised global embryonic transcriptome associated with advanced maternal age

Authors: Blair R. McCallie, Jason C. Parks, G. Devon Trahan, Kenneth L. Jones, Breanne D. Coate, Darren K. Griffin, William B. Schoolcraft, Mandy G. Katz-Jaffe

Published in: Journal of Assisted Reproduction and Genetics | Issue 5/2019

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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.
Appendix
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Literature
1.
Choi HW, Park YS, Lee SH, Lim CK, Seo JT, Yang KM. Effects of maternal age on embryo quality and pregnancy outcomes using testicular sperm with intracytoplasmic sperm injection. Clin Exp Reprod Med. 2016;43(4):221–7.CrossRefPubMedPubMedCentral
2.
3.
4.
Herbert M, Kalleas D, Cooney D, Lamb M, Lister L. Meiosis and maternal aging: insights from aneuploid oocytes and trisomy births. Cold Spring Harb Perspect Biol. 2015;7(4):a017970.CrossRefPubMedPubMedCentral
5.
Nybo Andersen AM, et al. Maternal age and fetal loss: population based register linkage study. BMJ. 2000;320(7251):1708–12.CrossRefPubMed
6.
Grande M, Borrell A, Garcia-Posada R, Borobio V, Munoz M, Creus M, et al. The effect of maternal age on chromosomal anomaly rate and spectrum in recurrent miscarriage. Hum Reprod. 2012;27(10):3109–17.CrossRefPubMed
7.
Braude P, Bolton V, Moore S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature. 1988;332(6163):459–61.CrossRefPubMed
8.
Miao YL, Kikuchi K, Sun QY, Schatten H. Oocyte aging: cellular and molecular changes, developmental potential and reversal possibility. Hum Reprod Update. 2009;15(5):573–85.CrossRefPubMed
9.
Igarashi H, Takahashi T, Nagase S. Oocyte aging underlies female reproductive aging: biological mechanisms and therapeutic strategies. Reprod Med Biol. 2015;14(4):159–69.CrossRefPubMedPubMedCentral
10.
Wang Q, Sun QY. Evaluation of oocyte quality: morphological, cellular and molecular predictors. Reprod Fertil Dev. 2007;19(1):1–12.CrossRefPubMed
11.
Zhao L, Lu T, Gao L, Fu X, Zhu S, Hou Y. Enriched endoplasmic reticulum-mitochondria interactions result in mitochondrial dysfunction and apoptosis in oocytes from obese mice. J Anim Sci Biotechnol. 2017;8:62.CrossRefPubMedPubMedCentral
12.
Miao YL, Williams CJ. Calcium signaling in mammalian egg activation and embryo development: the influence of subcellular localization. Mol Reprod Dev. 2012;79(11):742–56.CrossRefPubMedPubMedCentral
13.
14.
Lord T, Aitken RJ. Oxidative stress and ageing of the post-ovulatory oocyte. Reproduction. 2013;146(6):R217–27.CrossRefPubMed
15.
Dennery PA. Effects of oxidative stress on embryonic development. Birth Defects Res C Embryo Today. 2007;81(3):155–62.CrossRefPubMed
16.
Takahashi M. Oxidative stress and redox regulation on in vitro development of mammalian embryos. J Reprod Dev. 2012;58(1):1–9.CrossRefPubMed
17.
Ma P, Pan H, Montgomery RL, Olson EN, Schultz RM. Compensatory functions of histone deacetylase 1 (HDAC1) and HDAC2 regulate transcription and apoptosis during mouse oocyte development. Proc Natl Acad Sci U S A. 2012;109(8):E481–9.CrossRefPubMedPubMedCentral
18.
19.
Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403(6765):41–5.CrossRefPubMed
20.
Wang N, Tilly JL. Epigenetic status determines germ cell meiotic commitment in embryonic and postnatal mammalian gonads. Cell Cycle. 2010;9(2):339–49.CrossRefPubMed
21.
22.
Akiyama T, Nagata M, Aoki F. Inadequate histone deacetylation during oocyte meiosis causes aneuploidy and embryo death in mice. Proc Natl Acad Sci U S A. 2006;103(19):7339–44.CrossRefPubMedPubMedCentral
23.
Kawai K, Harada T, Ishikawa T, Sugiyama R, Kawamura T, Yoshida A, et al. Parental age and gene expression profiles in individual human blastocysts. Sci Rep. 2018;8(1):2380.CrossRefPubMedPubMedCentral
24.
Kuwayama M. Highly efficient vitrification for cryopreservation of human oocytes and embryos: the Cryotop method. Theriogenology. 2007;67(1):73–80.CrossRefPubMed
25.
26.
Wu TD, et al. GMAP and GSNAP for genomic sequence alignment: enhancements to speed, accuracy, and functionality. Methods Mol Biol. 2016;1418:283–334.CrossRefPubMed
27.
28.
Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28(5):511–5.CrossRefPubMedPubMedCentral
29.
Pfaffl MW, Horgan GW, Dempfle L. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 2002;30(9):e36.CrossRefPubMedPubMedCentral
30.
Shupnik MA. Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene. 2004;23(48):7979–89.CrossRefPubMed
31.
Wang X, Yan Z, Fulciniti M, Li Y, Gkotzamanidou M, Amin SB, et al. Transcription factor-pathway coexpression analysis reveals cooperation between SP1 and ESR1 on dysregulating cell cycle arrest in non-hyperdiploid multiple myeloma. Leukemia. 2014;28(4):894–903.CrossRefPubMed
32.
Metivier R, et al. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell. 2003;115(6):751–63.CrossRefPubMed
33.
Yao TP, Oh SP, Fuchs M, Zhou ND, Ch'ng LE, Newsome D, et al. Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell. 1998;93(3):361–72.CrossRefPubMed
34.
Brill A, Torchinsky A, Carp H, Toder V. The role of apoptosis in normal and abnormal embryonic development. J Assist Reprod Genet. 1999;16(10):512–9.CrossRefPubMedPubMedCentral
35.
Ooi YS, Stiles KM, Liu CY, Taylor GM, Kielian M. Genome-wide RNAi screen identifies novel host proteins required for alphavirus entry. PLoS Pathog. 2013;9(12):e1003835.CrossRefPubMedPubMedCentral
36.
Kawamura N, Sun-Wada GH, Aoyama M, Harada A, Takasuga S, Sasaki T, et al. Delivery of endosomes to lysosomes via microautophagy in the visceral endoderm of mouse embryos. Nat Commun. 2012;3:1071.CrossRefPubMed
37.
Liu Z, Shi H, Szymczak LC, Aydin T, Yun S, Constas K, et al. Promotion of bone morphogenetic protein signaling by tetraspanins and glycosphingolipids. PLoS Genet. 2015;11(5):e1005221.CrossRefPubMedPubMedCentral
38.
Graham SJ, et al. BMP signalling regulates the pre-implantation development of extra-embryonic cell lineages in the mouse embryo. Nat Commun. 2014;5:5667.CrossRefPubMed
39.
Lei X, et al. Bone morphogenetic protein 1 is expressed in porcine ovarian follicles and promotes oocyte maturation and early embryonic development. J Vet Med Sci. 2017;79(2):258–66.CrossRefPubMed
40.
Kodama A, Yoshino O, Osuga Y, Harada M, Hasegawa A, Hamasaki K, et al. Progesterone decreases bone morphogenetic protein (BMP) 7 expression and BMP7 inhibits decidualization and proliferation in endometrial stromal cells. Hum Reprod. 2010;25(3):751–6.CrossRefPubMed
41.
Martinovic S, Latin V, Suchanek E, Stavljenic-Rukavina A, Sampath KI, Vukicevic S. Osteogenic protein-1 is produced by human fetal trophoblasts in vivo and regulates the synthesis of chorionic gonadotropin and progesterone by trophoblasts in vitro. Eur J Clin Chem Clin Biochem. 1996;34(2):103–9.PubMed
42.
Monsivais D, Clementi C, Peng J, Fullerton PT Jr, Prunskaite-Hyyryläinen R, Vainio SJ, et al. BMP7 induces uterine receptivity and blastocyst attachment. Endocrinology. 2017;158(4):979–92.CrossRefPubMedPubMedCentral
43.
44.
Paliga AJ, Natale DR, Watson AJ. p38 mitogen-activated protein kinase (MAPK) first regulates filamentous actin at the 8-16-cell stage during preimplantation development. Biol Cell. 2005;97(8):629–40.CrossRefPubMed
45.
Thompson NA, Haefliger JA, Senn A, Tawadros T, Magara F, Ledermann B, et al. Islet-brain1/JNK-interacting protein-1 is required for early embryogenesis in mice. J Biol Chem. 2001;276(30):27745–8.CrossRefPubMed
46.
Bauersachs S, Mitko K, Ulbrich S, Blum H, Wolf E. Transcriptome studies of bovine endometrium reveal molecular profiles characteristic for specific stages of estrous cycle and early pregnancy. Exp Clin Endocrinol Diabetes. 2008;116(7):371–84.CrossRefPubMed
47.
Holtan SG, Creedon DJ, Haluska P, Markovic SN. Cancer and pregnancy: parallels in growth, invasion, and immune modulation and implications for cancer therapeutic agents. Mayo Clin Proc. 2009;84(11):985–1000.CrossRefPubMedPubMedCentral
48.
Delcuve GP, Khan DH, Davie JR. Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors. Clin Epigenetics. 2012;4(1):5.CrossRefPubMedPubMedCentral
49.
Stengel KR, Hiebert SW. Class I HDACs affect DNA replication, repair, and chromatin structure: implications for cancer therapy. Antioxid Redox Signal. 2015;23(1):51–65.CrossRefPubMedPubMedCentral
50.
Bhaskara S, Chyla BJ, Amann JM, Knutson SK, Cortez D, Sun ZW, et al. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell. 2008;30(1):61–72.CrossRefPubMedPubMedCentral
51.
Montgomery RL, Potthoff MJ, Haberland M, Qi X, Matsuzaki S, Humphries KM, et al. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J Clin Invest. 2008;118(11):3588–97.CrossRefPubMedPubMedCentral
52.
Verdel A, Seigneurin-Berny D, Faure AK, Eddahbi M, Khochbin S, Nonchev S. HDAC6-induced premature chromatin compaction in mouse oocytes and fertilised eggs. Zygote. 2003;11(4):323–8.CrossRefPubMed
53.
54.
Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 2005;6(8):611–22.CrossRefPubMed
55.
Robin JD, Ludlow AT, Batten K, Magdinier F, Stadler G, Wagner KR, et al. Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances. Genes Dev. 2014;28(22):2464–76.CrossRefPubMedPubMedCentral
56.
57.
Ozturk S, Sozen B, Demir N. Telomere length and telomerase activity during oocyte maturation and early embryo development in mammalian species. Mol Hum Reprod. 2014;20(1):15–30.CrossRefPubMed
58.
Kirkegaard K, Villesen P, Jensen JM, Hindkjær JJ, Kølvraa S, Ingerslev HJ, et al. Distinct differences in global gene expression profiles in non-implanted blastocysts and blastocysts resulting in live birth. Gene. 2015;571(2):212–20.CrossRefPubMed
Metadata
Title
Compromised global embryonic transcriptome associated with advanced maternal age
Authors
Blair R. McCallie
Jason C. Parks
G. Devon Trahan
Kenneth L. Jones
Breanne D. Coate
Darren K. Griffin
William B. Schoolcraft
Mandy G. Katz-Jaffe
Publication date
01-05-2019
Publisher
Springer US
Published in
Journal of Assisted Reproduction and Genetics / Issue 5/2019
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI
https://doi.org/10.1007/s10815-019-01438-5

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