Dynamic regulation of a domesticated DNA transposon-derived gene, in human germline and early embryonic development

Abstract

Embryonic development requires precise transcriptional regulation to guide transitions from totipotency to pluripotency and lineage specification. Transposable element (TE) derived genes are increasingly recognised as regulators of these processes, but the role of DNA transposon-derived factors remains poorly understood. Here, we investigate human embryogenesis, primordial germ cell (PGC) development, and gametogenesis, using bulk and single-cell transcriptomic and epigenomic datasets. We observe that THAP9, a domesticated DNA transposable element-derived gene, is selectively enriched in PGCs, but transiently silenced in somatic lineages. Moreover, the gene exhibits lineage-specific expression during pre-implantation development, peaking at the zygote stage, transiently paused during cleavage, reactivated at the morula, and remains enriched in trophectoderm and embryonic stem cells but repressed in primitive endoderm and epiblast. Interestingly, THAP9 is dynamically regulated across gametogenesis, with prominent expression in spermatids and germinal vesicle oocytes. Epigenomic profiling revealed progressive chromatin remodelling, including early bivalency and enhancer activation, consistent with roles in transcriptional reprogramming. These findings identify THAP9 as a germline-enriched, developmentally regulated gene with sex-specific functions in gametogenesis and pluripotency, advancing our understanding of how domesticated transposon-derived genes contribute to human reproduction and embryogenesis