F&S science · 2023
Endogenous retrotransposons cause catastrophic deoxyribonucleic acid damage in human trophoblasts.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Mauro Maurizio, Wei Shan, Breborowicz Andrzej, Li Xin, Bognanni Claudia, Fuller Zachary, Philipp Thomas, McDonald Torrin, Lattin Miriam Temmeh, Williams Zev
Аннотация
OBJECTIVE: To determine the mechanistic role of mobile genetic elements in causing widespread DNA damage in primary human trophoblasts.
DESIGN: Experimental ex vivo study.
SETTING: Hospital-affiliated University.
PATIENT(S): Trophoblasts from a patient with unexplained recurrent pregnancy loss and patients with spontaneous and elective abortions (n = 10).
INTERVENTION(S): Biochemical and genetic analysis and modification of primary human trophoblasts.
MAIN OUTCOME MEASURE(S): To phenotype and systematically evaluate the underlying pathogenic mechanism for elevated DNA damage observed in trophoblasts derived from a patient with unexplained recurrent pregnancy loss, transcervical embryoscopy, G-band karyotyping, RNA sequencing, quantitative polymerase chain reaction, immunoblotting, biochemical and siRNA assays, and whole-genome sequencing were performed.
RESULT(S): Transcervical embryoscopy revealed a severely dysmorphic embryo that was euploid on G-band karyotyping. RNA sequencing was notable for markedly elevated LINE-1 expression, confirmed with quantitative polymerase chain reaction, and that resulted in elevated expression of LINE-1-encoded proteins, as shown by immunoblotting. Immunofluorescence, biochemical and genetic approaches demonstrated that overexpression of LINE-1 caused reversible widespread genomic damage and apoptosis.
CONCLUSION(S): Derepression of LINE-1 elements in early trophoblasts results in reversible but widespread DNA damage.
DESIGN: Experimental ex vivo study.
SETTING: Hospital-affiliated University.
PATIENT(S): Trophoblasts from a patient with unexplained recurrent pregnancy loss and patients with spontaneous and elective abortions (n = 10).
INTERVENTION(S): Biochemical and genetic analysis and modification of primary human trophoblasts.
MAIN OUTCOME MEASURE(S): To phenotype and systematically evaluate the underlying pathogenic mechanism for elevated DNA damage observed in trophoblasts derived from a patient with unexplained recurrent pregnancy loss, transcervical embryoscopy, G-band karyotyping, RNA sequencing, quantitative polymerase chain reaction, immunoblotting, biochemical and siRNA assays, and whole-genome sequencing were performed.
RESULT(S): Transcervical embryoscopy revealed a severely dysmorphic embryo that was euploid on G-band karyotyping. RNA sequencing was notable for markedly elevated LINE-1 expression, confirmed with quantitative polymerase chain reaction, and that resulted in elevated expression of LINE-1-encoded proteins, as shown by immunoblotting. Immunofluorescence, biochemical and genetic approaches demonstrated that overexpression of LINE-1 caused reversible widespread genomic damage and apoptosis.
CONCLUSION(S): Derepression of LINE-1 elements in early trophoblasts results in reversible but widespread DNA damage.