Primate-specific Transcription Factors & Cis-Regulatory Elements Regulate Human Developmental Evolution.

The human genome is composed of 4.5 million transposable elements (TE). The requirement for a TE to propagate through the genome during evolution is to be expressed to be retro-transpose into germ cells or pre-implantation embryo. Thus, many evolutionarily young TEs still contain DNA binding sites for pluripotency factors and are transiently expressed in the pre-implantation embryo. We observed that these and many other primate-restricted transposable elements have alternative binding sites for cell-type-specific transcription factors that allow them to be transcribed during human gastrulation. Furthermore, we have demonstrated that they can also serve as cell-type-specific enhancers and induce the expression of KRAB-Zinc Finger repressors of similar evolutionary age. This mechanism allows the domestication of TEs containing cell-type-specific binding sites and their incorporation into the shaping of human developmental-specific transcription networks. Overall design: RNA-seq and Single-nuclei Multi-omic (ATAC and RNA) in endoderm and gastruloid differentiated human embryonic stem cells