CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis

Nishiyama, M et al. 2009. Nature Cell Biology 11: 172 – 182

Speaker: 陳奐勻                                                         Time: 15:10~16:00, Apr. 22, 2009

Commentator: 劉校生老師                                        Place: Room 601

Abstract:

Apoptosis, or programmed cell death, is an essential part of life for any multicellular organism. However, it is not fully understood how apoptosis is regulated during embryogenesis. The tumor-suppressor protein p53 has an important pro-apoptotic function. Many of the effects of p53 are mediated through the transcriptional activation or repression of downstream targets. The chromodomain helicase DNA-binding (CHD) family of enzymes was first discovered and characterized in mice during a search for regulators of immunoglobulin promoters. It is thought to regulate gene expression, but their role in specific gene regulation has been unclear. Among these proteins, CHD8 (duplin) is a protein involved in β-catenin and Wnt signaling pathway. Moreover, CHD8 interacts with CTCF (CCCTC- binding factor) which is an insulator binding protein known to regulate transcription. In this study, the authors showed that CHD8 is expressed at a high level during early embryogenesis and prevents apoptosis mediated by p53. Conversely, depletion of both CHD8_S and CHD8_L by RNA interference (RNAi) induced cell apoptosis. By using a ‘shotgun’ proteomics approach to find that histone H1 was consistently the most prominent of the proteins associated with immunoprecipitated Flag–CHD8_S. In addition, deletion of p53 or CHD8 binding domains markedly impaired the ability of CHD8_S to recruit histone H1. Together, these data suggest that CHD8 negatively regulates p53 function by recruiting histone H1, resulting in suppression of apoptosis triggered by p53. These observations reveal a mode of p53 regulation mediated by CHD8, which provide further genetic evidence in support of a crucial role for CHD8 in development.

References:

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2.      Hall JA, Georgel PT. 2007. CHD proteins: a diverse family with strong ties. Biochem Cell Biol 85: 463-476.