Endogenous retrotransposons cause catastrophic deoxyribonucleic acid damage in human trophoblasts

To determine the mechanistic role of mobile genetic elements in causing widespread DNA damage in primary human trophoblasts.

Experimental ex vivo study.

Hospital-affiliated University.

Trophoblasts from a patient with unexplained recurrent pregnancy loss and patients with spontaneous and elective abortions (n = 10).

Biochemical and genetic analysis and modification of primary human trophoblasts.

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.

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.

Derepression of LINE-1 elements in early trophoblasts results in reversible but widespread DNA damage.