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Publications

Journal Article Epublish

PubMed: 41827883 DOI: 10.3390/cells15050450

Acute Depletion of Cited2 in Embryonic Stem Cells Disrupts Gene Networks Controlling Self-Renewal, Homeostasis, and Early Cell Fate Commitment.

Cells 15(5)

Authors: Leonardo Mendes-Silva, Sara M Brigida, Marlene Trindade, João M A Santos, Lucas Rougier, Rui Machado, Ana Luísa Escapa, Agapios Sachinidis, Jessica L MacDonald, José Bragança

Affiliations

  • Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal. Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal.
  • Department of Biology, Program in Neuroscience, Syracuse University, 107 College Place, Syracuse, NY 13244, USA.
  • Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal.
  • Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal.
  • Center for Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany.
  • RISE-Health, University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.

Abstract

Cited2 is a transcriptional regulator essential for embryonic development and cellular homeostasis. Studies in vertebrate models highlight its critical roles in heart, placental, neural tube, and hematopoietic development. In humans, CITED2 variants are associated with congenital heart disease. Functionally, Cited2 interacts with the transcriptional co-regulators p300/CBP and modulates the activity of multiple transcription factors. In embryonic stem cells (ESC), Cited2 supports pluripotency, self-renewal, and differentiation potential. Here, we performed comparative transcriptomic analysis after acute Cited2 depletion in mouse ESC to define its role in maintaining self-renewal, lineage competence, and cell survival. 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 decreased cell viability at least in part involving p53. Comparison with p300-, CBP-, and Cited2-depletion datasets revealed only partial overlap between affected gene sets. These results position Cited2 as a core regulator preserving ESC identity, genomic stability, and proper lineage engagement during early differentiation.

MeSH

Cells, Genes, Embryonic Stem Cells, Gene Regulatory Networks, Microscopy, Electron, Scanning Transmission, Cell Survival, Homeostasis, Heart, Stem Cells