Exploring the role of SAMHD1 in deoxynucleotide metabolism in human naive pluripotent stem cells via CRISPRi-mediated gene silencing

The regulation of deoxynucleotide (dNTP) metabolism in human naive pluripotent stem cells (hPSCs) remains poorly characterized, despite its fundamental importance for genome integrity, cellular identity, and the maintenance of pluripotency. A deeper understanding of these pathways is crucial to clarify the molecular mechanisms governing early human development and stem cell function. Here, we investigated the role of the dNTPase SAMHD1 in naive hPSCs using transcriptional analyses, biochemical quantification of dNTP pools, and an inducible CRISPR interference (CRISPRi) system for targeted gene repression. These findings position SAMHD1 as a key regulator of nucleotide metabolism and telomere maintenance in naive hPSCs and provide a versatile platform to further dissect SAMHD1-related genome stability pathways and disease mechanisms, including those underlying Aicardi-Goutières syndrome.