CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis.
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.
Nishiyama
Masaaki
M
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
Oshikawa
Kiyotaka
K
Tsukada
Yu-ichi
Y
Nakagawa
Tadashi
T
Iemura
Shun-ichiro
S
Natsume
Tohru
T
Fan
Yuhong
Y
Kikuchi
Akira
A
Skoultchi
Arthur I
AI
Nakayama
Keiichi I
KI
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006367:HeLa Cells; D006657:Histones / Q000235:genetics*; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D015820:Cadherins; C504541:Cdh8 protein, mouse; D006657:Histones; D046911:Macromolecular Substances; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53