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

Abstract

The chromodomain helicase DNA-binding (CHD) family of enzymes is thought to regulate gene expression, but their role in the regulation of specific genes has been unclear. Here we show that CHD8 is expressed at a high level during early embryogenesis and prevents apoptosis mediated by the tumour suppressor protein p53. CHD8 was found to bind to p53 and to suppress its transactivation activity. CHD8 promoted the association of p53 and histone H1, forming a trimeric complex on chromatin that was required for inhibition of p53-dependent transactivation and apoptosis. Depletion of CHD8 or histone H1 resulted in p53 activation and apoptosis. Furthermore, Chd8−/− mice died early during embryogenesis, manifesting widespread apoptosis, whereas deletion of p53 ameliorated this developmental arrest. These observations reveal a mode of p53 regulation mediated by CHD8, which may set a threshold for induction of apoptosis during early embryogenesis by counteracting p53 function through recruitment of histone H1.

One-by-One Sample Preparation Method for Protein Network Analysis

“…However, because it is possible to reliably identify low amounts of true interacting proteins by improving the signal-to-noise ratio in LC-MS/MS, we considered that reproducibly decreasing the level of nonspecific noise proteins in single-step purification samples would be a valid approach. Therefore, we empirically developed and optimized the conditions for sample preparation, and using this methodology, found more than fifty significant protein-protein interactions (Hirano et al, 2005;Kitajima et al, 2006;Iioka et al, 2007;Komatsu et al, 2007;Nishiyama et al, 2009;Kaneko et al, 2009;Komatsu et al, 2010). In spite of this useful methodology, we realized the limitations of the existing preparation method in large-scale analysis, because we found that the amount of true interactors, as well as nonspecific proteins, in manually parallel-prepared samples varied.…”

The ATP-dependent chromatin remodeling enzyme CHD7 regulates pro-neural gene expression and neurogenesis in the inner ear

“…Other members of the CHD protein family have been implicated in proliferation and/or apoptosis (Bagchi et al, 2007;Gaspar-Maia et al, 2009;Nishiyama et al, 2009;Rodriguez-Paredes et al, 2009). In vitro inhibition of Chd1 creates abnormally high levels of neural differentiation, and is required for maintenance of pluripotency (Gaspar-Maia et al, 2009).…”

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

“…In contrast to the rare isolated mutations in these three CHD genes, 13 different recurrent alleles of CHD8 have been observed in individuals with ASD/ID in association with macrocephaly and gastrointestinal disturbance [66,70,[75][76][77][78]. In cultured cells, CHD8 has been shown to bind CHD7 and to both bind and regulate p53 and inhibit its proapoptotic effects during development; thus, it is surprising that loss of CHD8 is not associated with broader phenotypic effects in humans [79][80][81][82]. Knockdown of Chd8 by shRNA does not alter the morphology or neural ectodermal markers of neural progenitors derived from human iPS cells, but does significantly impair their gene expression [74].…”