Korablev, A. N. | bioRxiv Science

bioRxiv2025

Pcbp1 orchestrates amino acid metabolism burst during the naive-to-primed pluripotency transition

Embryo implantation is accompanied by the naive-to-primed pluripotency transition in epiblast cells, making them receptive to external differentiation signals. In addition to this developmental program switch, implantation suggests that an anabolic boost is required for this process, as the embryo-uterine connection begins supplying the requisite nutrients. In this study, we show that the DNA-binding protein Pcbp1 plays a key role in intensifying amino acid metabolism during the priming of pluripotent stem cells. Knockout of the Pcbp1 gene leads to embryo growth arrest a few days after implantation. By modeling the naive-to-primed pluripotency transition in vitro, we observe reduced proliferation and induction of apoptosis in cells deficient for Pcbp1. Using multi-omics approaches, we uncover a crucial role for Pcbp1 in driving a transcriptional burst of numerous genes involved in the import and the de novo synthesis of essential and conditionally essential amino acids. Pcbp1 deficiency is consequently associated with a slowdown in protein biosynthesis, explaining the early lethal phenotype of knockout embryos. Our findings thus uncover the molecular mechanisms underlying anabolic changes during the naive-to-primed pluripotency transition and highlight the essential role of Pcbp1 in this process, also pointing to its functions in highly proliferative cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/658314v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1e17b48org.highwire.dtl.DTLVardef@64e940org.highwire.dtl.DTLVardef@10d6b00org.highwire.dtl.DTLVardef@1ec0d23_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2024

Direction and modality of transcription changes caused by TAD boundary disruption in Slc29a3/Unc5b locus depends on tissue-specific epigenetic context

Topologically associated domains (TADs) are believed to be involved in the regulation of gene expression. While the impact of TAD perturbations is usually studied in developmental genes with highly cell-type-specific expression patterns, this study examines genes with broad expression profiles divided by a strong insulatory boundary. We focused on mouse Slc29a3/Unc5b locus, which encompasses two distinct TADs. Our analysis demonstrates that deletions of CTCF binding sites within this locus lead to alterations in local chromatin architecture, disrupting existing loops and forming novel long-range interactions. We evaluated the transcription changes of Unc5b, Slc29a3, Psap, Vsir, Cdh23, and Sgpl1 genes across various organs, finding that TAD boundary disruption results in variable transcriptional responses, where not only magnitude, but also direction of gene expression changes are tissue-specific. Current models of genome architecture, including enhancer competition and hijacking, only partially account for these transcriptional changes, indicating the need for further investigation into the mechanisms underlying TAD function and gene regulation.

genetics↗