Abstract
LINE-1 (Long Interspersed Nuclear elements) and HERVs (Human Endogenous Retroviruses) are two families of retrotransposons which together account for about 28% of the human genome. Genes harbored within LINE-1 and HERV retrotransposons, particularly that encoding the reverse transcriptase (RT) enzyme, are generally expressed at low levels in differentiated cells, but their expression is up-regulated in embryonic tissues and transformed cells. Here we review evidence indicating that the LINE-1-encoded RT plays regulatory roles in early embryonic development. Indeed, antisense-mediated inhibition of expression of a highly expressed LINE-1 family in mouse zygotes caused developmental arrest at the two- or four-cell embryo stages. Development is also arrested when the embryo endogenous RT activity is pharmacologically inhibited by nevirapine, an RT inhibitor currently employed in AIDS treatment. The arrest of embryonic development is irreversible even after RT inhibition is removed and it is associated with subverted gene expression profiles. These data indicate an early requirement for LINE-1-encoded RT to support early developmental progression. Consistent with this, recent findings indicate that a reverse transcription wave is triggered in the zygote a few hours after fertilization and is propagated at least through the first two rounds of cell division. On the whole these findings suggest that reverse transcription is strictly required in early embryos as a key component of a novel RT-dependent mechanism that regulated the proper unfolding of the developmental program.
Highlights
On the whole these findings suggest that reverse transcription is strictly required in early embryos as a key component of a novel reverse transcriptase (RT)-dependent mechanism that regulated the proper unfolding of the developmental program
A priori the embryonic RT can be of two possible sources: (i) autonomously synthesized in early embryos via transcription of LINE-1 and ERV families, whose expression is reactivated concomitant with genome demethylation; (ii) non-mutually exclusively, RT may be carried over by spermatozoa at fertilization
Currently in progress, we have found that sperm cells deliver functional RT to oocytes at fertilization, which has a precocious role in the zygote, as revealed by the occurrence of reverse transcription enzymatic activity predominantly in the male pronucleus
Summary
The earliest stages of embryogenesis, from fertilization to the second cell division, identify a crucial window during which many essential genome-wide events occur simultaneously and shape the subsequent developmental program. Several genetic and epigenetic events are activated in this developmental frame, e.g., the fusion of paternal and maternal genomes, genome demethylation, chromatin remodeling in pronuclei, activation of embryonic gene expression and genome replication These events do affect the earliest stages of development, but they activate the molecular machinery responsible for early blastomere commitment with far-reaching implications for development of the growing embryo. Differentiated gametes to first return to full totipotency [3], and later restrict the totipotency of early blastomeres to support cell fate determination In consequence of these epigenetic and conformational changes both parental genomes, within only a few hours after fertilization, acquire the competence to replicate and activate embryonic gene expression under zygotic control, which replaces the maternally inherited control at fertilization. The molecular mechanisms underlying these processes are largely obscure: both the basis of their timing and their mutual links remain to be clarified in this intricate program
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