Summary Transposable Elements (TEs) account for ~50% of the human genome, and several lines of evidence now suggest an extensive role for these parasitic elements as a critical source of gene-regulatory novelty in mammals. In this context, my laboratory aims at unveiling the mechanisms that TEs adopt to regulate and rewire mammalian gene regulatory networks. In particular, the fundamental problem that we aim to solve is how a very recent genomic invasion by young mobile elements (SINE-VNTR-Alus = SVAs) has set the ground for human-specific traits. Among the 5 main TE classes, SVAs are the youngest, and include 7 subfamilies being either hominid- specific (SVA-A, -B, -C, and -D) or human-specific (SVA-E, -F, and F1). Importantly, SVAs are still replication competent in humans, and over 60% of the existing human SVA copies are located within 10 kb of a coding gene. Given their young age, SVAs are particularly relevant for understanding human evolution. Our preliminary data show that genes proximal to human-specific SVA insertions are enriched for biological processes associated with brain development, craniofacial morphology, and cognitive behavior. Moreover, SVAs are among the most epigenetically de-repressed and transcriptionally upregulated TEs across a multitude of cancers. Our recent work demonstrated that the large majority of human-specific enhancers and promoters contain SVA insertions, and that SVA transposition within enhancer bodies correlates with either increased or decreased associated gene expression, with well-defined tissue-specific patterns. In spite of the conspicuous lines of evidence suggesting that SVAs are important regulators of human gene expression, we still have limited knowledge of the biology of these TEs. For example, we do not know the mechanism by which SVAs enhance AND repress transcriptional activity on host genes, tissues-specifically. We do not know which component(s) of the modular structure of these TEs drives the regulatory activity. Finally, and more importantly, we do not know the relative contribution of human-specific SVAs to the rewiring of human-specific regulatory networks, and to the generation of human specific traits. To fill these gaps of knowledge, we will apply our genomic expertise to human and chimpanzee's induced Pluripotent Stem Cell differentiation, using hippocampal neurogenesis as a proof of principle. Moreover, to address the mechanism, we will harness human cell-lines, CRISPR/Cas9, and genomics. We will deconstruct the complex modular architecture of SVAs, and define the mechanism adopted by SVAs to drive regulatory activity on the host genome. We will delve into the tissue-specific repressive activity displayed by select SVAs to uncover the underlying mechanism, also testing the hypothesis that a subset of SVAs offers a genome-wide substrate for a critical transcriptional repressor (YY1). With the proposed research we will gain transformative insights on how human-specific traits are generated, and we will shed light on why the dysregulation of SVAs is so frequently observed in disease, including cancer and neurological disorders.