Roles of ErbB3-binding protein 1 (EBP1) in embryonic development and gene-silencing control

다국어 초록 (Multilingual Abstract)

<P><B>Significance</B></P><P><I>Ebp1</I> deletion causes developmental defects with massive cell death and cessation of cell proliferation through dysregulation of epigenetic gene silencing unit, a Suv39H1/DNMT1 axis. Our study indicates that EBP1 regulates global gene expression via at least 2 mechnaisms. First, EBP1 acts as a transcriptional repressor for DNMT1 gene expression, allowing the escape of the repressive chromatin state. Second, EBP1 binds to the promoter region of the target gene inhibiting the association of DNMT1 with the downstream gene such as <I>Survivin</I>, regulating gene expression. Hence, these findings provide a molecular mechanism of how EBP1 functions in cell survival and transcriptional regulation by modulating epigenetic regulators during development.</P><P>ErbB3-binding protein 1 (EBP1) is implicated in diverse cellular functions, including apoptosis, cell proliferation, and differentiation. Here, by generating genetic inactivation of <I>Ebp1</I> mice, we identified the physiological roles of EBP1 in vivo. Loss of <I>Ebp1</I> in mice caused aberrant organogenesis, including brain malformation, and death between E13.5 and 15.5 owing to severe hemorrhages, with massive apoptosis and cessation of cell proliferation. Specific ablation of Ebp1 in neurons caused structural abnormalities of brain with neuron loss in [Nestin-Cre; <I>Ebp1</I><SUP><I>flox/flox</I></SUP>] mice. Notably, global methylation increased with high levels of the gene-silencing unit Suv39H1/DNMT1 in <I>Ebp1</I>-deficient mice. EBP1 repressed the transcription of <I>Dnmt1</I> by binding to its promoter region and interrupted DNMT1-mediated methylation at its target gene, <I>Survivin</I> promoter region. Reinstatement of EBP1 into embryo brain relived gene repression and rescued neuron death. Our findings uncover an essential role for EBP1 in embryonic development and implicate its function in transcriptional regulation.</P>