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Transcriptome-Wide piRNA Profiling in Human Brains for Aging Genetic FactorsMao, Qiao, Fan, Longhua, Wang, Xiaoping, Lin, Xiandong, Cao, Yuping, Zheng, Chengchou, Zhang, Yong, Zhang, Huihao, Garcia-Milian, Rolando, Kang, Longli, Shi, Jing, Yu, Ting, Wang, Kesheng, Zuo, Lingjun, Li, Chiang-Shan R., Guo, Xiaoyun, Luo, Xingguang 01 January 2019 (has links)
OBJECTIVE: Piwi-interacting RNAs (piRNAs) represent a molecular feature shared by all nonaging biological systems, including the germline and somatic cancer stem cells, which display an indefinite renewal capacity and lifespan-stable genomic integrity and are potentially immortal. Here, we tested the hypothesis that piRNA is a critical genetic determinant of aging in humans. METHODS: Expression of transcriptome-wide piRNAs (n=24k) was profiled in the human prefrontal cortex of 12 subjects (84.9±9.5, range 68-100, years of age) using microarray technology. We examined the correlation between these piRNAs' expression levels and age, adjusting for covariates including disease status. RESULTS: A total of 9,453 piRNAs were detected in brain. Including seven intergenic and three intronic piRNAs, ten piRNAs were significantly associated with age after correction for multiple testing (|r|=0.9; 1.9×10≤p≤9.9×10). CONCLUSION: We conclude that piRNAs might play a potential role in determining the years of survival of humans. The underlying mechanisms might involve the suppression of transposable elements (TEs) and expression regulation of aging-associated genes.
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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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