Protein Arginine Methyltransferase 5 (Prmt5) Promotes Gene Expression of Peroxisome Proliferator-Activated Receptor γ2 (PPARγ2) and Its Target Genes during Adipogenesis

Abstract

Regulation of adipose tissue formation by adipogenic-regulatory proteins has long been a topic of interest given the ever-increasing health concerns of obesity and type 2 diabetes in the general population. Differentiation of precursor cells into adipocytes involves a complex network of cofactors that facilitate the functions of transcriptional regulators from the CCATT/enhancer binding protein, and the peroxisome proliferator-activated receptor (PPAR) families. Many of these cofactors are enzymes that modulate the structure of chromatin by altering histone-DNA contacts in an ATP-dependent manner or by posttranslationally modifying the histone proteins. Here we report that inhibition of protein arginine methyltransferase 5 (Prmt5) expression in multiple cell culture models for adipogenesis prevented the activation of adipogenic genes. In contrast, overexpression of Prmt5 enhanced adipogenic gene expression and differentiation. Chromatin immunoprecipitation experiments indicated that Prmt5 binds to and dimethylates histones at adipogenic promoters. Furthermore, the presence of Prmt5 promoted the binding of ATP-dependent chromatin-remodeling enzymes and was required for the binding of PPARγ2 at PPARγ2-regulated promoters. The data indicate that Prmt5 acts as a coactivator for the activation of adipogenic gene expression and promotes adipogenic differentiation.

The Scaffold attachment factor b1 (Safb1) regulates myogenic differentiation by facilitating the transition of myogenic gene chromatin from a repressed to an activated state

“…For example, SWI/SNF chromatin remodelling enzymes are required for the differentiation of most tissue types (57,58) yet are reported to act as negative regulators of transcription at specific stages of some tissue differentiation events (59) and during ES cell differentiation (60–62). The arginine methyltransferase Prmt5, like Safb1, was initially characterized as a negative regulator of gene expression yet was subsequently shown to be required for both myogenic- and adipogenic-specific gene expression and differentiation (28,63,64). The functional activity of each of these regulators is likely the same regardless of context; positive or negative outcomes with regard to transcriptional regulation are almost certainly dependent on the local chromatin environment in which the regulator functions.…”

The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction

“…It can be concluded that the DNA methylome of mature adipocytes develops early in the lineage differentiation, and that the large majority of adipocyte genes is 'ready' for transcriptional induction as early as the preadipocyte stage. The limiting and necessary factor is PPARγ2, whose expression and DNA binding activity are controlled by epigenetic mechanisms during adipogenesis (Fujiki et al, 2009;LeBlanc et al, 2012;Wang et al, 2013a,b). Interestingly, the expression of PPARγ2 was reduced in the adipose tissue of diabetic mice, and this was due to repressive methylation of its promoter region (Fujiki et al, 2009), indicating that DNA methylation of PPARγ2 is important for adipose tissue (dys)function.…”

PRMT5 inhibition promotes osteogenic differentiation of mesenchymal stromal cells and represses basal interferon stimulated gene expression

“…Specific interaction of PRMT5 with cooperator of PRMT5 (Co-Pr5) is required for PRMT5 nuclear functions especially in symmetric arginine dimethylation on histone H4 (H4R3me2s) [5]. Prmt5 deletion is embryonic lethal in mouse and is required for proliferation and/or differentiation of several stem cell lineages including ES cells [6], skeletal muscle stem cells [7–9], adipose stem cells [10], hematopoietic stem and progenitors [11], chondrocyte progenitors [12] among others. PRMT5 is also required for important cellular processes such as maintenance of chromatin states [13], cell cycle and RNA splicing [14].…”