A product of BMI1 gene, a key component of the Polycomb family, positively regulates adipocyte differentiation of mouse mesenchymal stem cells

Abstract

Bmi1 is a key component of the Polycomb (PcG) family, which in mammals regulates the basic properties of somatic stem cells (SSC): self-renewal and differentiation. Bmi1 supports SSC via transcriptional suppression of genes associated with cell cycle and differentiation. The best studied targets of Bmi1 are Ink4 locus genes p14^Arf and p16^Ink4a, an inhibitor of cyclin-dependent kinases. Their suppression due to BMI1 activating mutations results in generation of cancer stem cells (CSC) and carcinomas in various tissues. In contrast, inactivation of BMI1 results in cell cycle arrest and cell senescence. Although clinical phenomena of BMI1 hypo- and hyperactivation are well known, its targets and role in the regulation of tissue specific SSC are largely unknown. The goal of this study was to evaluate the regulatory role of BMI1 in adipocyte differentiation (AD) of mouse mesenchymal stem cells (MSC). AD induction in mouse C3H10T1/2 cell line was accompanied with increased expression of BMI1, pRb family genes (RB, p130) and demethylase UTX, but not methyltransferase EZH2 methylated H3K27. H3K27me3 plays the role of an AD epigenetic switch in human MSC (Hemming et. al., 2014). BMI1 inactivation using specific siRNA slowed and decreased AD but did not abolish it. It was accompanied with total inhibition of expression of adipogenic markers PPARγ2, ADIPOQ and RB, p130 but not UTX. These results provide evidence that epigenetic mechanisms regulating AD differentiation in mouse and human MSC are different.