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Dysregulated trophoblast-specific gene expression mediated by retroviral regulatory sequences contributes to preeclampsia (PE)Anwar, Rabia 11 March 2021 (has links)
Präeklampsie (PE) ist eine Komplikation, die während der Schwangerschaft auftritt, fast 2-8% aller Schwangerschaften betrifft und human spezifisch ist. PE ist eine der Hauptursachen für den Tod von Mutter und Kind. Eine abnormale Plazentaentwicklung aufgrund einer verminderten Trophoblasteninvasion und einem gestörten Umbau der Spiralarterien trägt zur Pathogenese der PE bei. Klinisch wird die PE durch Bluthochdruck und Proteinurie, auftretendnach der 20. Schwangerschaftswoche, diagnostiziert und kann durch eine Funktionsstörung von Organen begleitet werden. Bei besonders schweren Verläufen ist die frühzeitige Endbindung die letzte Möglichkeit das Überleben der Mutter zu gewährleisten.
Das Ziel dieser Studie ist es, weitere Gene zu identifizieren, die durch ERVs in der menschlichen Plazenta spezifisch reguliert werden und in PE dysreguliert sind. Um dieses Ziel zu erreichen, wurde das Transkriptom von primären menschlichen Trophoblastenzellen von 5 gesunden und 5 früh einsetzenden PE-Plazenten mittels RNA-Sequenzierung analysiert. Es wurden 335 Gene identifiziert, welche eine höhere Expression in den Trophoblastenzellen im Vergleich zu anderen Geweben aufwiesen. Zusätzlich zeigten einige der Gene (n=88) eine Co-Regulation der Expression durch retrovirale LTRs (10-kb 5‘ des transcription start side (TSS) des Gens). Hauptinteresse lag hierbei auf den Genen, welche ebenfalls eine Dysregulation in der PE aufwiesen (n = 16).
Diese Studie identifizierte EPS8L1, das durch primaten-spezifisches ERV-LTR (MLT1G1) in Trophoblastenzellen reguliert wird, als einen wichtigen Faktor in der Entwicklung der menschlichen Plazenta. EPS8L1 ist in der PE Plazenta dysreguliert und involviert in mehrere Signalwege und die Funktionalität von Trophoblasten wie Invasion, Angiogenese und Redoxhomöostase. Hierdurch führt diese Arbeit zu einem besseren Verständnis der PE und deren human-spezifischer Natur. / Preeclampsia (PE) is a complication that occurs during pregnancy and affects almost 2-8% of all pregnancies and is often regarded as a human-specific disorder.1,2 PE is one of the major causes of maternal and fetal death.1 Failure of the trophoblast cells to invade into the maternal decidua results in the improper remodeling of spiral arteries leading to PE pathogenesis. Clinically, it is diagnosed as a maternal syndrome, diagnosed by the new-onset of hypertension and proteinuria or other end-organ dysfunction after the 20th week of pregnancy. So far, the only effective treatment of the disorder is the removal of the placenta tissue and delivery of the infant.
The aim of this study is to identify additional genes that are regulated by the human ERV-LTRs in the human placenta specifically, and are dysregulated in PE. To achieve this aim, the transcriptome of primary human trophoblast cells of 5 healthy and 5 early-onset PE placentas were analyzed by RNA sequencing (RNA-seq). RNA-seq analysis identified genes (n=335) with stronger expression in the trophoblast cells as compared to other human body tissues. Additionally, some of the genes (n=88) showed co-regulation of expression by the human ERV-LTRs in their vicinity (10-kb upstream of transcription start side (TSS) of the gene). Since my interest was to identify the new targets of PE pathogenesis, so I focused on genes (n=16) with dysregulated expression in women presented with PE.
This study identified a new gene EPS8L1, regulated by primate-specific ERV-LTR in trophoblast cells that has a predominant role in the human placenta development and demonstrated that its dysregulation affected multiple pathways involved in trophoblast function like invasion, angiogenesis and maintenance of cell redox homeostasis. Furthermore, this study leads to the better understanding of the disease by explaining certain aspects of human-specific nature of PE.
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The Role of APOBEC3 in Controlling Retroviral Spread and ZoonosesRosales Gerpe, María Carla January 2014 (has links)
APOBEC3 (A3) proteins are a family of host-encoded cytidine deaminases that protect against retroviruses and other viral intruders. Retroviruses, unlike other viruses, are able to integrate their genomic proviral DNA within hours of entering host cells. A3 proteins hinder retroviral infectivity by editing retroviral replication intermediates, as well as by inhibiting retroviral replication and integration through deamination-independent methods. These proteins thus constitute the first line of immune defense against endogenous and exogenous retroviral pathogens. The overall goal of my Master's project was to better understand the critical role A3 proteins play in restricting inter- and intra-host transmission of retroviruses. There are two specific aspects that I focused on: first, investigating the role of mouse APOBEC3 (mA3) in limiting the zoonotic transmission of murine leukemia retroviruses (MLVs) in a rural environment; second, to identify the molecular features in MLVs that confer susceptibility or resistance to deamination by mA3. For the first part of my project, we collected blood samples from dairy and production cattle from four different geographical locations across Canada. We then designed a novel PCR screening strategy targeting conserved genetic regions in MLVs and Mouse Mammary Tumor Virus (MMTV) and MMTV-like betaretroviruses. Our results indicate that 4% of animals were positive for MLV and 2% were positive for MMTV. Despite crossing the species barrier by gaining entry into bovine cells, our study also demonstrates that the bovine A3 protein is able to potently inhibit the spread of these murine retroviruses in vitro. The next question we asked was whether mA3 could also mutate and restrict murine endogenous retroviruses and thereby partake in limiting zoonotic transmission. Moloney MLV and AKV MLV are two highly homologous murine gammaretroviruses with opposite sensitivities to restriction by mA3: MoMLV is resistant to restriction and deamination while AKV is sensitive to both. Design of MoMLV/AKV hybrid viruses enabled us to map the region of mA3 resistance to the region encoding the glyco-Gag accessory protein. Site-directed mutagenesis then allowed us to correlate the number of N-linked glycosylation sites with the level of resistance to deamination by mA3. Our results suggest that Gag glycosylation is a possible viral defence mechanism that arose to counteract the evolutionary pressure imposed by mA3. Overall, my projects show the important role A3 proteins play in intrinsic immunity, whether defending the host from foreign retroviral invaders or endogenous retroviral foes.
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