Protein interaction network for pluripotency of ES cells: Possible clues to organization of self-renewal machinery in other stem cells

摘要

In light of inherent difficulties in identifying components of the self-renewal machinery of hematopoietic stem cells (HSCs) in a comprehensive and systematic fashion, we have turned to embryonic stem (ES) cells as a tractable alternative. ES cells are pluripotent and capable of indefinite self-renewal. Understanding pluripotency at the molecular level should illuminate fundamental properties of stem cells. The cell-specific, atypical homeodomain protein Nanog is thought to function in concert with other factors such as Oct4 and Sox2 to establish ES cell identity. We have explored the protein network in which Nanog operates in mouse ES cells. Following affinity purification of Nanog and mass spectrometry, we have identified physically associated proteins. In an iterative fashion, we also identified partners of several Nanog-associated proteins (including Oct4), validated the functional relevance of selected newly identified components, and constructed a protein interaction network. The network is highly enriched for nuclear factors that are critical individually for maintenance of the ES cell state and co-regulated on differentiation. The network is linked to multiple corepressor pathways, and comprised of numerous proteins whose encoding genes are putative direct transcriptional targets of its members. This tight protein network would appear to constitute a cellular module dedicated to pluripotency. Possible implications of these findings for other types of stem cells, such as HSCs, will be considered.