Abstract
Transition from pluripotency to differentiation is a pivotal yet poorly understood developmental step. Here, we show that the tumour suppressor RASSF1A is a key player driving the early specification of cell fate. RASSF1A acts as a natural barrier to stem cell self-renewal and iPS cell generation, by switching YAP from an integral component in the β-catenin-TCF pluripotency network to a key factor that promotes differentiation. We demonstrate that epigenetic regulation of the Rassf1A promoter maintains stemness by allowing a quaternary association of YAP-TEAD and β-catenin-TCF3 complexes on the Oct4 distal enhancer. However, during differentiation, promoter demethylation allows GATA1-mediated RASSF1A expression which prevents YAP from contributing to the TEAD/β-catenin-TCF3 complex. Simultaneously, we find that RASSF1A promotes a YAP-p73 transcriptional programme that enables differentiation. Together, our findings demonstrate that RASSF1A mediates transcription factor selection of YAP in stem cells, thereby acting as a functional "switch" between pluripotency and initiation of differentiation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Cycle Proteins
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Cell Differentiation
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DNA-Binding Proteins / metabolism
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Embryonic Stem Cells / cytology*
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Embryonic Stem Cells / physiology
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Female
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Gene Expression Regulation, Developmental
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Hippo Signaling Pathway
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Humans
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Male
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Mice, Inbred C57BL
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Mice, Inbred CBA
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction
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TEA Domain Transcription Factors
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Transcription Factors / metabolism
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Tumor Protein p73 / genetics
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Tumor Protein p73 / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Wnt Proteins / metabolism
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YAP-Signaling Proteins
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beta Catenin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Basic Helix-Loop-Helix Transcription Factors
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CTNNB1 protein, mouse
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Cell Cycle Proteins
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DNA-Binding Proteins
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Octamer Transcription Factor-3
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Phosphoproteins
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Pou5f1 protein, mouse
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RASSF1 protein, human
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RASSF1 protein, mouse
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TEA Domain Transcription Factors
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Tcf3 protein, mouse
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Tead2 protein, mouse
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Transcription Factors
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Trp73 protein, mouse
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Tumor Protein p73
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Tumor Suppressor Proteins
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Wnt Proteins
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YAP-Signaling Proteins
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Yap1 protein, mouse
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beta Catenin
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Protein Serine-Threonine Kinases