Acute depletion of Cited2 in embryonic stem cells disrupts gene networks controlling self-renewal, homeostasis, and early cell fate commitment

Loss of Cited2 rapidly destabilized the pluripotency network and induced aberrant activation of developmental gene programs. Nodal/Activin pathway targets, including key regulators of mesoderm, cardiac, and neural development, were markedly downregulated, consistent with Cited2-null embryonic phenotypes. Cited2 depletion also altered the expression of genes involved in DNA damage response, immune signaling, and apoptosis, correlating with the increased γH2AX accumulation and p53-dependent viability loss observed.

Comparison with p300- and CBP-depletion datasets revealed minimal overlap, supporting a largely p300/CBP-independent role for Cited2 in ESC. These results position Cited2 as a core regulator preserving ESC identity, genomic stability, and proper lineage engagement during early differentiation.