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Dissertation Thesis Phd Dysregulated Trophoblast-Specific Gene

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Dissertation Thesis Phd Dysregulated Trophoblast-Specific Gene Dysregulated trophoblast-specific gene expression mediated by retroviral regulatory sequences contributes to preeclampsia (PE) Dissertation zur Erlangung des akademischen Grades Doctor of Philosophy (PhD) im Fach Biologie eingereicht an der Lebenswissenschaftlichen Fakultät der Humboldt-Universität zu Berlin von Master of Science Rabia Anwar Präsident der Humboldt-Universität zu Berlin Prof. Dr.-Ing. Dr. Sabine Kunst Dekan der der Lebenswissenschaftlichen Fakultät Prof. Dr. Bernhard Grimm Gutachter: 1. Prof. Dr. Ana Pombo 2. Prof. Dr. Kai Schmidt-Ott 3. Dr. Zsuzsanna Izsvák Tag der mündlichen Prüfung: 30th September 2020 i Content Content Summary ................................................................................................................................... 1 Zusammenfassung .................................................................................................................... 3 1. Background and Introduction......................................................................................... 5 1.1. Preeclampsia (PE) ............................................................................................................. 5 1.2. Healthy pregnancy ............................................................................................................ 6 1.2.1. Placenta development in a healthy pregnancy ................................................................. 6 1.2.2. Placenta tissue composition ............................................................................................. 8 1.3. Incidence of PE .................................................................................................................. 9 1.4. Classification of PE ........................................................................................................... 9 1.5. Risk factors of PE ............................................................................................................ 10 1.6. Pathophysiology of PE .................................................................................................... 10 1.7. Epigenetics and PE .......................................................................................................... 14 1.8. Epigenetics and activation of transposable elements (TEs) ........................................ 15 1.9. Transposable elements (TEs) ......................................................................................... 16 1.10. Tissue-specific regulation by TEs ................................................................................ 16 1.11. Types of TEs .................................................................................................................. 17 1.11.1. Retrotransposons .......................................................................................................... 17 1.12. Role of LTR retrotransposons in human placenta development .............................. 18 1.12.1. Placenta-specific genes derived from endogenous retroviruses (ERVs) ..................... 19 1.12.2. Placenta-specific promoters and enhancers co-opted from human endogenous retroviral LTRs (ERV-LTRs) ................................................................................................... 21 1.13. Objectives of the study .................................................................................................. 23 2. Materials and methods ................................................................................................... 25 2.1. Materials .......................................................................................................................... 25 2.1.1. mRNA isolation, quantitative polymerase chain reaction (q-PCR) ........................ 25 2.1.2. Primers and sgRNAs .................................................................................................... 25 2.1.3. Western blot .................................................................................................................. 30 2.1.4. Flow cytometry ............................................................................................................. 31 2.1.5. Immunostaining and immunohistochemistry ............................................................ 31 2.1.6. Isolation of primary human trophoblasts .................................................................. 32 2.1.7. Cell transfection ............................................................................................................ 33 2.1.8. Mass spectrometry ....................................................................................................... 33 2.1.9. Reagents and kits for assays ........................................................................................ 34 2.1.10. Chemicals .................................................................................................................... 34 2.1.11. Software ....................................................................................................................... 34 2.1.12. Hardware .................................................................................................................... 34 2.2. Methods ............................................................................................................................ 35 2.2.1. Patient cohorts .............................................................................................................. 35 2.2.2. Primary human trophoblast isolation ........................................................................ 37 2.2.3. Primary human trophoblasts mRNA isolation and sequencing .............................. 39 2.2.4. Trophoblast-specific genes (TSGs) and transposable elements (TEs) expression analysis .................................................................................................................................... 41 2.2.5. Quantitative polymerase chain reaction (q-PCR) ..................................................... 43 2.2.6. Single cell RNA-seq (scRNA-seq) data analysis ........................................................ 44 2.2.7. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) data analysis ....... 44 2.2.8. Cell culture .................................................................................................................... 45 2.2.9. Genomic DNA extraction ............................................................................................. 45 ii Content 2.2.10. ERV-LTR constructs ................................................................................................. 46 2.2.11. GFP reporter assay .................................................................................................... 46 2.2.12. Western blot ................................................................................................................ 47 2.2.13. Enzyme linked immunosorbent assay (ELISA) of EPS8L1 ................................... 47 2.2.14. Immunohistochemistry (IHC) staining of primary villi and term placenta tissue (human) ................................................................................................................................... 48 2.2.15. Immunostaining of EPS8L1 in SGHPL-4 cells ........................................................ 48 2.2.16. Knock-out (KO) of EPS8L1 ....................................................................................... 49 2.2.17. Overexpression (OE) of EPS8L1 ............................................................................... 50 2.2.18. Mass spectrometry (MS) of EPS8L1 ........................................................................ 50 2.2.19. EPS8L1 overexpression (OE) and transcriptome analysis ..................................... 51 2.2.20. Intersection of PE patients and OE-EPS8L1_SGHPL-4 cells datasets ................. 53 2.2.21. Invasion assay ............................................................................................................. 54 2.2.22. Tube formation assay (Angiogenesis assay) ............................................................. 55 2.2.23. DCFH-DA assay (ROS assay) ................................................................................... 55 2.2.24. Statistics ....................................................................................................................... 55 3. Results ............................................................................................................................. 57 3.1. Search strategy to identify trophoblast-specific genes associated with ERV-LTRs . 57 3.2. Expression of trophoblast-specific genes in PE patients.............................................. 61 3.3. Trophoblast-specific expression of dysregulated genes in PE ..................................... 63 3.4. ERV-LTR mediated trophoblast-specific gene regulation .......................................... 65 3.5. Functional characterization of EPS8L1 in PE .............................................................. 67 3.6. Expression and localization of EPS8L1 in human placenta tissue ............................. 68 3.7. EPS8L1 is upregulated in PE but not in IUGR patients ............................................. 69 3.8. EPS8L1 expression correlates with the prognostic marker of PE .............................. 72 3.9. EPS8L1 knock-out (KO) in trophoblast cells ............................................................... 72 3.10. Characterization of EPS8L1-protein interactors by mass spectrometry
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