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Functional analysis of Sall4 in modulating embryonic stem cell fate

  • Author(s): Lee, Pei Jen A.
  • et al.
Abstract

Cell fate decisions of embryonic stem (ES) cells are dictated by repression and activation of lineage-specific genes. How are those regulators important in activating a stem cell to begin differentiating into a specific cell type regulated by the cellular and molecular signals? Understanding how these lineages arise during development will illuminate efforts to understand the establishment and maintenance of the stem cell state and the mechanisms that restrict stem cell potency. Sall4 has been reported to be part of the core transcriptional network in embryonic stem cells; however, how Sall4 regulates ES cell fate is still unknown. I utilized mass spectrometry to generate whole ES cell proteomes and phosphoproteomes of human and mouse ES cells. The whole cell proteomic and phosphoproteomic analysis provides us a large repertoire of protein lists to unmask the regulatory elements in ES cells. Moreover, I generated a novel list of Sall4-binding proteins by modifying a previously established enrichment protocol. Our findings demonstrate the effectiveness of using a synthetic crosslinker, DSP, to enrich for weak and transient Sall4 interacting protein complexes. Working with molecular weight cut-off columns, allows us to identify new Sall4 binding partners, leading to a better understanding of the regulatory machinery behind the self- renewal and pluripotency of ES cells. Pathway analysis indicates that Sall4-binding proteins are involved in Wnt signaling pathway, FGF signaling pathway, and p53 pathway. Our data indicates that the ES cell proliferation defect may be regulated by Integrin, TGF-beta, Cadherin, and PI3K signaling pathways. Furthermore, the interactome has led me to explore a possible novel function of Sall4 in microRNA biogenesis. By understanding how Sall4 regulates cell fate determination can substantially push ESC research forward

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