The Autism-Related Protein CHD8 Cooperates with C/EBPβ to Regulate Adipogenesis

Yasuyuki Kita; Yuta Katayama; Taichi Shiraishi; Takeru Oka; Tetsuya Sato; Mikita Suyama; Yasuyuki Ohkawa; Keishi Miyata; Yuichi Oike; Michiko Shirane; Masaaki Nishiyama; Keiichi I Nakayama

doi:10.1016/j.celrep.2018.04.050

The Autism-Related Protein CHD8 Cooperates with C/EBPβ to Regulate Adipogenesis

Cell Rep. 2018 May 15;23(7):1988-2000. doi: 10.1016/j.celrep.2018.04.050.

Authors

Affiliations

¹ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan; Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
² Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
³ Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
⁴ Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
⁵ Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
⁶ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan; Department of Histology and Cell Biology, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan. Electronic address: nishiyam@staff.kanazawa-u.ac.jp.
⁷ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. Electronic address: nakayak1@bioreg.kyushu-u.ac.jp.

PMID: 29768199
DOI: 10.1016/j.celrep.2018.04.050

Abstract

The gene encoding the chromatin remodeler CHD8 is the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Heterozygous mutations in CHD8 give rise to ASD that is often accompanied by macrocephaly, gastrointestinal complaints, and slender habitus. Whereas most phenotypes of CHD8 haploinsufficiency likely result from delayed neurodevelopment, the mechanism underlying slender habitus has remained unknown. Here, we show that CHD8 interacts with CCAAT/enhancer-binding protein β (C/EBPβ) and promotes its transactivation activity during adipocyte differentiation. Adipogenesis was impaired in Chd8-deleted preadipocytes, with the upregulation of C/EBPα and peroxisome-proliferator-activated receptor γ (PPARγ), two master regulators of this process, being attenuated in mutant cells. Furthermore, mice with CHD8 ablation in white preadipocytes had a markedly reduced white adipose tissue mass. Our findings reveal a mode of C/EBPβ regulation by CHD8 during adipogenesis, with CHD8 deficiency resulting in a defect in the development of white adipose tissue.

Keywords: ASD; C/EBP; CCAAT/enhancer-binding protein; Chd8; PPARγ; adipogenesis; autism; chromatin remodeler.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Adipocytes / metabolism
Adipocytes / pathology
Adipogenesis* / genetics
Adipose Tissue, White / pathology
Animals
Autistic Disorder / metabolism*
CCAAT-Enhancer-Binding Protein-alpha / metabolism
CCAAT-Enhancer-Binding Protein-beta / metabolism*
DNA-Binding Proteins / metabolism*
Gene Expression Regulation
Genome
HEK293 Cells
Humans
Hypertrophy
Mice
Mice, Inbred C57BL
PPAR gamma / metabolism
Protein Binding

Substances

CCAAT-Enhancer-Binding Protein-alpha
CCAAT-Enhancer-Binding Protein-beta
DNA-Binding Proteins
PPAR gamma
duplin protein, mouse