RRC ID 54721
Author Hirota A, Nakajima-Koyama M, Ashida Y, Nishida E.
Title The nucleosome remodeling and deacetylase complex protein CHD4 regulates neural differentiation of mouse embryonic stem cells by down-regulating p53.
Journal J. Biol. Chem.
Abstract Lineage specification of the three germ layers occurs during early embryogenesis and is critical for normal development. The nucleosome remodeling and deacetylase (NuRD) complex is a repressive chromatin modifier that plays a role in lineage commitment. However, the role of chromodomain helicase DNA-binding protein 4 (CHD4), one of the core subunits of the NuRD complex, in neural lineage commitment is poorly understood. Here, we report that the CHD4/NuRD complex plays a critical role in neural differentiation of mouse embryonic stem cells (ESCs). We found that RNAi-mediated Chd4 knockdown suppresses neural differentiation, as did knockdown of methyl-CpG-binding domain protein Mbd3, another NuRD subunit. Chd4 and Mbd3 knockdowns similarly affected changes in global gene expression during neural differentiation and up-regulated several mesendodermal genes. However, inhibition of mesendodermal genes by knocking out the master regulators of mesendodermal lineages, Brachyury and Eomes, through a CRISPR/Cas9 approach could not restore the impaired neural differentiation caused by the Chd4 knockdown, suggesting that CHD4 controls neural differentiation by not repressing other lineage differentiation processes. Notably, Chd4 knockdown increased the acetylation levels of p53, resulting in increased protein levels of p53. Double knockdown of Chd4 and p53 restored the neural differentiation rate. Furthermore, overexpression of BCL2, a downstream factor of p53, partially rescued the impaired neural differentiation caused by the Chd4 knockdown. Our findings reveal that the CHD4/NuRD complex regulates neural differentiation of ESCs by down-regulating p53.
Volume 294(1)
Pages 195-209
Published 2019-1-4
DOI 10.1074/jbc.RA118.004086
PII RA118.004086
PMID 30409903
PMC PMC6322895
MeSH Animals Cell Differentiation* Cell Line DNA Helicases / genetics DNA Helicases / metabolism* Down-Regulation* Gene Knockdown Techniques Mice Mouse Embryonic Stem Cells Neurons / cytology Neurons / metabolism* Nucleosomes / genetics Nucleosomes / metabolism* Proto-Oncogene Proteins c-bcl-2 / biosynthesis Proto-Oncogene Proteins c-bcl-2 / genetics Tumor Suppressor Protein p53 / biosynthesis* Tumor Suppressor Protein p53 / genetics
IF 4.011
Resource
Human and Animal Cells EBRTcH3(AES0054)