Epigenetic and transcriptional effects of full-length LINE-1 retrotransposons in human neural progenitor cells

Abstract: Transposable elements (TE) are parasitic genetic entities that have the ability to alter their position within a genome and have the potential to influence its functionality. Although TEs play beneficial roles in the evolution of their host, they are active in various human disorders including neurological diseases, where may contribute to the progress of the disease. Long Interspersed Nuclear Element-1(LINE-1, L1) is the dominant, autonomously-transposing TE family in all mammals and some the evolutionary-young LINE-1s are thought to be active in human neural progenitor cells (NPCs). We defined the epigenetic environment and transcriptional activity of the seven evolutionary-youngest L1 subfamilies in human NPCs, and compared this profile to human endogenous retroviruses (HERVs). Our analysis of two heterochromatin associated histone methylation marks (H3K9me3, H3K27me3) suggested that H3K9me3 is responsible for silencing a majority of the studied TEs, whereas H3K27me3 is significantly less present. Profiling of two epigenetic marks associated with transcriptional activity (H3K4me1, H3K4me3) revealed that the presence of H3K4me3 is a better predicter of LINE-1 transcription than H3K4me1 for those elements that evade repression. Furthermore, we investigated the transcriptional differences between human and chimpanzee NPCs, focusing in particular on genes containing human-specific LINE-1 elements (L1HS). We found 11 genes containing a full-length L1HS sequence that showed downregulation in human compared to the chimpanzee NPCs. A Chi-square test suggested dependency between the presence of L1HS and thedownregulation of genes, perhaps due to induction of H3K9me3-heterchromatin. Looking ahead, this project provides a base for further exploration of functional roles of LINE-1 elements in human NPCs and a template to investigate mechanisms of LINE-1 and HERV regulation by chromatin regulators