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J Biol Chem. 2015 Feb 13;290(7):4163-77. doi: 10.1074/jbc.M114.626929. Epub 2014 Dec 22.

The FBXL10/KDM2B scaffolding protein associates with novel polycomb repressive complex-1 to regulate adipogenesis.

Author information

1
From the Division of Metabolic Medicine, the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, inagaki@lsbm.org.
2
From the Division of Metabolic Medicine.
3
the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, Laboratory for Systems Biology and Medicine.
4
From the Division of Metabolic Medicine, the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, Laboratory for Systems Biology and Medicine.
5
From the Division of Metabolic Medicine, the Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
6
From the Division of Metabolic Medicine, the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan.
7
Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
8
the Metabolic Disease Program, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, and.
9
the Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
10
the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
11
Laboratory for Systems Biology and Medicine.
12
From the Division of Metabolic Medicine, the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, jmsakai-tky@umin.ac.jp.

Abstract

Polycomb repressive complex 1 (PRC1) plays an essential role in the epigenetic repression of gene expression during development and cellular differentiation via multiple effector mechanisms, including ubiquitination of H2A and chromatin compaction. However, whether it regulates the stepwise progression of adipogenesis is unknown. Here, we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. Knockdown of either RING1B or SKP1 prevented FBXL10-mediated repression of 3T3-L1 preadipocyte differentiation indicating that PRC1 formation mediates the inhibitory effect of FBXL10 on adipogenesis. Using ChIP-seq, we show that FBXL10 recruits RING1B to key specific genomic loci surrounding the key cell cycle and the adipogenic genes Cdk1, Uhrf1, Pparg1, and Pparg2 to repress adipogenesis. These results suggest that FBXL10 represses adipogenesis by targeting a noncanonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage.

KEYWORDS:

3T3-L1 cells; Adipocyte; Adipogenesis; Cell Differentiation; FBXL10/KDM2B/JHDM1B; Mitotic Clonal Expansion (MCE); Peroxisome Proliferator-activated Receptor (PPAR); Polycomb; Polycomb Repressive Complex 1 (PRC1); RING1B

PMID:
25533466
PMCID:
PMC4326826
DOI:
10.1074/jbc.M114.626929
[Indexed for MEDLINE]
Free PMC Article

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