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Histone demethylase KDM5A is transactivated by the transcription factor C/EBPβ and promotes preadipocyte differentiation by inhibiting Wnt/β-catenin signaling.
J Biol Chem. 2019 06 14; 294(24):9642-9654.JB

Abstract

β-Catenin signaling is triggered by WNT proteins and is an important pathway that negatively regulates adipogenesis. However, the mechanisms controlling the expression of WNT proteins during adipogenesis remain incompletely understood. Lysine demethylase 5A (KDM5A) is a histone demethylase that removes trimethyl (me3) marks from lysine 4 of histone 3 (H3K4) and serves as a general transcriptional corepressor. Here, using the murine 3T3-L1 preadipocyte differentiation model and an array of biochemical approaches, including ChIP, immunoprecipitation, RT-qPCR, and immunoblotting assays, we show that Kdm5a is a target gene of CCAAT/enhancer-binding protein β (C/EBPβ), an important early transcription factor required for adipogenesis. We found that C/EBPβ binds to the Kdm5a gene promoter and transactivates its expression. We also found that siRNA-mediated KDM5A down-regulation inhibits 3T3-L1 preadipocyte differentiation. The KDM5A knockdown significantly up-regulates the negative regulator of adipogenesis Wnt6, having increased levels of the H3K4me3 mark on its promoter. We further observed that WNT6 knockdown significantly rescues adipogenesis inhibited by the KDM5A knockdown. Moreover, we noted that C/EBPβ negatively regulates Wnt6 expression by binding to the Wnt6 gene promoter and repressing Wnt6 transcription. Further experiments indicated that KDM5A interacts with C/EBPβ and that their interaction cooperatively inhibits Wnt6 transcription. Of note, C/EBPβ knockdown impaired the recruitment of KDM5A to the Wnt6 promoter, which had higher H3K4me3 levels. Our results suggest a mechanism involving C/EBPβ and KDM5A activities that down-regulates the Wnt/β-catenin pathway during 3T3-L1 preadipocyte differentiation.

Authors+Show Affiliations

From the Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China liangguo@fudan.edu.cn.From the Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China.From the Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China.From the Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China.From the Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China qqtang@shmu.edu.cn.

Pub Type(s)

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

Language

eng

PubMed ID

31061100

Citation

Guo, Liang, et al. "Histone Demethylase KDM5A Is Transactivated By the Transcription Factor C/EBPβ and Promotes Preadipocyte Differentiation By Inhibiting Wnt/β-catenin Signaling." The Journal of Biological Chemistry, vol. 294, no. 24, 2019, pp. 9642-9654.
Guo L, Guo YY, Li BY, et al. Histone demethylase KDM5A is transactivated by the transcription factor C/EBPβ and promotes preadipocyte differentiation by inhibiting Wnt/β-catenin signaling. J Biol Chem. 2019;294(24):9642-9654.
Guo, L., Guo, Y. Y., Li, B. Y., Peng, W. Q., & Tang, Q. Q. (2019). Histone demethylase KDM5A is transactivated by the transcription factor C/EBPβ and promotes preadipocyte differentiation by inhibiting Wnt/β-catenin signaling. The Journal of Biological Chemistry, 294(24), 9642-9654. https://doi.org/10.1074/jbc.RA119.008419
Guo L, et al. Histone Demethylase KDM5A Is Transactivated By the Transcription Factor C/EBPβ and Promotes Preadipocyte Differentiation By Inhibiting Wnt/β-catenin Signaling. J Biol Chem. 2019 06 14;294(24):9642-9654. PubMed PMID: 31061100.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Histone demethylase KDM5A is transactivated by the transcription factor C/EBPβ and promotes preadipocyte differentiation by inhibiting Wnt/β-catenin signaling. AU - Guo,Liang, AU - Guo,Ying-Ying, AU - Li,Bai-Yu, AU - Peng,Wan-Qiu, AU - Tang,Qi-Qun, Y1 - 2019/05/06/ PY - 2019/03/12/received PY - 2019/05/03/revised PY - 2019/5/8/pubmed PY - 2020/2/26/medline PY - 2019/5/8/entrez KW - 3T3-L1 preadipocyte KW - C/EBPbeta KW - CCAAT/enhancer-binding protein (C/EBP) KW - ChIP-on-chip KW - Wnt signaling KW - Wnt/beta-catenin pathway KW - adipogenesis KW - beta-catenin (B-catenin) KW - chromatin immunoprecipitation (ChiP) KW - epigenetics KW - fat cell KW - histone demethylase KW - lysine demethylase 5A (KDM5A) KW - obesity KW - post-translational modification (PTM) SP - 9642 EP - 9654 JF - The Journal of biological chemistry JO - J Biol Chem VL - 294 IS - 24 N2 - β-Catenin signaling is triggered by WNT proteins and is an important pathway that negatively regulates adipogenesis. However, the mechanisms controlling the expression of WNT proteins during adipogenesis remain incompletely understood. Lysine demethylase 5A (KDM5A) is a histone demethylase that removes trimethyl (me3) marks from lysine 4 of histone 3 (H3K4) and serves as a general transcriptional corepressor. Here, using the murine 3T3-L1 preadipocyte differentiation model and an array of biochemical approaches, including ChIP, immunoprecipitation, RT-qPCR, and immunoblotting assays, we show that Kdm5a is a target gene of CCAAT/enhancer-binding protein β (C/EBPβ), an important early transcription factor required for adipogenesis. We found that C/EBPβ binds to the Kdm5a gene promoter and transactivates its expression. We also found that siRNA-mediated KDM5A down-regulation inhibits 3T3-L1 preadipocyte differentiation. The KDM5A knockdown significantly up-regulates the negative regulator of adipogenesis Wnt6, having increased levels of the H3K4me3 mark on its promoter. We further observed that WNT6 knockdown significantly rescues adipogenesis inhibited by the KDM5A knockdown. Moreover, we noted that C/EBPβ negatively regulates Wnt6 expression by binding to the Wnt6 gene promoter and repressing Wnt6 transcription. Further experiments indicated that KDM5A interacts with C/EBPβ and that their interaction cooperatively inhibits Wnt6 transcription. Of note, C/EBPβ knockdown impaired the recruitment of KDM5A to the Wnt6 promoter, which had higher H3K4me3 levels. Our results suggest a mechanism involving C/EBPβ and KDM5A activities that down-regulates the Wnt/β-catenin pathway during 3T3-L1 preadipocyte differentiation. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/31061100/Histone_demethylase_KDM5A_is_transactivated_by_the_transcription_factor_C/EBPβ_and_promotes_preadipocyte_differentiation_by_inhibiting_Wnt/β_catenin_signaling_ DB - PRIME DP - Unbound Medicine ER -