Epigenetic Modulation of Short Interspersed Nuclear Elements Activity Influences Neural Precursor Cell Proliferation

Abstract

Abstract Transposable elements (TEs) play a critical role in modulating gene expression during neurodevelopment. Short Interspersed Nuclear Elements (SINEs), a significant subset of TEs, contribute to gene regulation by generating non-coding transcripts and functioning as enhancers. Moreover, SINEs harbor binding sites for the CCCTC-binding factor (CTCF), pivotal in orchestrating chromatin organization. However, the exact function of SINEs in neurodevelopment remains elusive. In our study, we conducted a comprehensive genome-wide analysis using ATAC-seq, ChIP-seq, WGBS, in situ Hi-C, and RNA-seq. We elucidated the intricate epigenetic regulations governing a relatively conserved subset of SINEs in mouse neural precursor cells (NPCs). Our findings revealed that the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) orchestrates H3K9me3, in conjunction with DNA methylation, to restrict SINEs' chromatin accessibility in NPCs. Loss of SETDB1 granted CTCF access to previously restricted SINE elements, facilitating novel chromatin loop formation and influencing cell cycle genes. Disruptions in cell proliferation were notably observed both in vitro and in vivo following genetic ablation of SETDB1 in NPCs. In summary, our study sheds light on the comprehensive epigenetic regulation of SINEs, suggesting their role in maintaining chromatin integrity and stemness in NPCs.