title: RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery.
abstract: Recurrent pregnancy loss (RPL) concerns ~3% of couples aiming at childbirth. In the current study, transcriptomes and miRNomes of 1sttrimester placental chorionic villi were analysed for 2 RPL cases (≥6 miscarriages) and normal, but electively terminated pregnancies (ETP; n = 8). Sequencing was performed on Illumina HiSeq 2000 platform. Differential expression analyses detected 51 (27%) transcripts with increased and 138 (73%) with decreased expression in RPL compared to ETP (DESeq: FDR P < 0.1 and DESeq2: <0.05). RPL samples had substantially decreased transcript levels of histones, regulatory RNAs and genes involved in telomere, spliceosome, ribosomal, mitochondrial and intra-cellular signalling functions. Downregulated expression of HIST1H1B and HIST1H4A (Wilcoxon test, fc≤0.372, P≤9.37 × 10-4) was validated in an extended sample by quantitative PCR (RPL, n = 14; ETP, n = 24). Several upregulated genes are linked to placental function and pregnancy complications: ATF4, C3, PHLDA2, GPX4, ICAM1, SLC16A2. Analysis of the miRNA-Seq dataset identified no large disturbances in RPL samples. Notably, nearly 2/3 of differentially expressed genes have binding sites for E2F transcription factors, coordinating mammalian endocycle and placental development. For a conceptus destined to miscarriage, the E2F TF-family represents a potential key coordinator in reprogramming the placental genome towards gradually stopping the maintenance of basic nuclear and cellular functions.
authors.affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Riia St. 23, 51010 Tartu, Estonia.
authors.forename: Siim
authors.initials: S
authors.lastname: Sõber
authors.affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Riia St. 23, 51010 Tartu, Estonia.|Department of Obstetrics and Gynaecology, University of Tartu, L. Puusepa St. 8, Tartu 51014, Estonia.|Women's Clinic of Tartu University Hospital, L. Puusepa St. 8, Tartu 51014, Estonia.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Rull
authors.affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Riia St. 23, 51010 Tartu, Estonia.
authors.forename: Mario
authors.initials: M
authors.lastname: Reiman
authors.affiliation: Department of Genetics, United Laboratories of Tartu University Hospital, L. Puusepa St. 2, Tartu 51014, Estonia.
authors.forename: Piret
authors.initials: P
authors.lastname: Ilisson
authors.affiliation: The Institute for Molecular Medicine Finland (FIMM), Tukholmankatu 8, Helsinki FI-00014 Finland.|Finnish Red Cross Blood Service (FRCBS), Kivihaantie 7, Helsinki FI-00310, Finland.
authors.forename: Pirkko
authors.initials: P
authors.lastname: Mattila
authors.affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Riia St. 23, 51010 Tartu, Estonia.|Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila St. 19, 50412 Tartu, Estonia.
authors.forename: Maris
authors.initials: M
authors.lastname: Laan
mesh_terms: D000026:Abortion, Habitual / Q000235:genetics* / Q000503:physiopathology; D001665:Binding Sites; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002824:Chorionic Villi / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D017423:Sequence Analysis, RNA; D059467:Transcriptome / Q000235:genetics*
chemical_list: D050684:E2F Transcription Factors; C104345:H1-5 protein, human; D006657:Histones; D035683:MicroRNAs