Regulation of adipogenesis by nucelar receptor PPARγ is modulated by the histone demethylase JMJD2C

Abstract

A potential strategy to combat obesity and its associated complications involves modifying gene expression in adipose cells to reduce lipid accumulation. The nuclear receptor Peroxisome Proliferator-activated receptor gamma (PPARγ) is the master regulator of adipose cell differentiation and its functional activation is currently used as a therapeutic approach for Diabetes Mellitus type 2. However, total activation of PPARγ induces undesirable secondary effects that might be set with a partial activation. A group of proteins that produce histone demethylation has been shown to modify the transcriptional activity of nuclear receptors. Here we describe the repressive action of the jumonji domain containing 2C/lysine demethylase 4 C (JMJD2C/KDM4C) on PPARγ transcriptional activation. JMJD2C significantly reduced the rosiglitazone stimulated PPARγ activation. This effect was mainly observed in experiments performed using the Tudor domains that may interact with histone deacetylase class 1 (HDAC) and this interaction probably reduces the mediated activation of PPARγ. Trichostatin A, a HDAC inhibitor, reduces the repressive effect of JMJD2C. When JMJD2C was over-expressed in 3T3-L1 cells, a reduction of differentiation was observed with the Tudor domain. In summary, we herein describe JMJD2C-mediated reduction of PPARgamma transcriptional activation as well as preadipocyte differentiation. This novel action of JMJD2C might have an important role in new therapeutic approaches to treat obesity and its complications.

Role of Histone Demethylases in Cardiomyocytes Induced to Hypertrophy

“…It has been demonstrated that JMJD2C is preferentially expressed in undifferentiated embryonic stem cells (ESCs) and regulates self-renewal in ESCs [ 24 ]. We previously observed the reduction of adipose cell differentiation after JMJD2C overexpression in mesenchymal progenitors; in accordance with our results it is probable that the role of JMJD2C in cardiac hypertrophic development might be limited [ 25 ]. On the other hand, UTX, like JMJD3, has a preferential H3K27 demethylase function, which has been important to the differentiation process of cardiac cells from mesodermal precursors [ 21 , 26 ].…”

The Histone Demethylase JMJD2A Modulates the Induction of Hypertrophy Markers in iPSC-Derived Cardiomyocytes

“…JMJD2C plays a role in embryonic cells both in the renewal of pluripotency itself and as a regulator of embryonic cell differentiation ( Das et al, 2014 ; Tomaz et al, 2017 ). We observed a reduction in the differentiation capacity of pluripotent mesenchymal adipose cells after JMJD2C overexpression in human subcutaneous adipose tissue ( Lizcano et al, 2011 ). Our results indicate that the role of JMJD2C in the development of cardiac hypertrophy is likely limited.…”

The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells

“…Both KDM4A and KDM4C are known to be important in development, such as in mouse embryonic stem cells ( 9 , 39 ). KDM4C has been shown to slow adipogenesis by attenuating the activity of the nuclear receptor PPARγ ( 40 ). It has also been reported that KDM4C interacts with KDM1A to collaboratively regulate the expression of androgen receptor-dependent genes ( 41 ).…”