The transcription factor SRF regulates MERVL retrotransposons and gene expression during zygotic genome activation

The regulatory circuitry of cell-specific transcriptional programmes is thought to be influenced by transposable elements (TEs) whereby TEs serve as raw material for the diversification and genome-wide distribution of genetic elements that contain cis-regulatory elements. However, the transcriptional activators of TEs in relevant physiological contexts are largely unknown. Here, we undertook an evolutionary approach to identify regulators of two main families of MERVL, a major regulator of transcription during early mouse development. Using a combination of phyloregulatory, transcriptomics and loss-of-function approaches we demonstrate that SRF is a novel regulator of MERVL and of embryonic transcription during zygotic genome activation. By resolving the phylogenetic history of two major MERVL families, we delineate the evolutionary acquisition of SRF and DUX binding sites and show that the acquisition of the SRF site precedes that of DUX. SRF contributes to embryonic transcription through the regulation of MERVLs, which in turn serves as promoter for host genes. Our work identifies new transcriptional regulators and TEs that shape the gene expression programmes in early embryos and highlights the process of TE domestication via the sequential acquisition of transcription factor binding sites and co- evolution with the host. Mouse embryos (zygotes) were microinjected with a dominant negative construct of SRF (SRF-LOF), antisense oligos against DUX (DUX-LOF) or in combination (DOUBLE LOF), cultured until the late 2-cell stage and collected for Smart-Seq+5' an adapation protocol of Smart-Seq2