PRODUCT OF THE BMI1 - A KEY COMPONENT OF POLYCOMB - POSITIVELY REGULATES ADIPOCYTE DIFFERENTIATION OF MOUSE MESENCHYMAL
STEM CELLS
N.S. Petrov, N.A. Vereschagina, E.N. Sushilova, A.V. Kropotov, N.F. Miheeva, B.V. Popov 1
Institute of Cytology RAS, St. Petersburg, 194064;
1 e-mail: borisvp478@gmail.com
Bmi1 is a key component of Polycomb (PcG), which in mammals controls the basic functions of mammalian somatic stem cells (SSC) such as self-renewal and differentiation.
Bmi1 supports SSC via transcriptional suppression of genes associated with cell cycle and differentiation. The most studied target genes of Bmi1 are the genes of Ink4 locus,
CdkI ð16Ink4a and p14Arf, suppression of which due to activating mutations of the BMI1 results in formation 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 hypo- and
hyperactivation of BMI1 are well known, its targets and mechanisms of regulation of tissue specific SSC are still obscure. The goal of this study was to evaluate the regulatory
role of BMI1 in adipocyte differentiation (AD) of mouse mesenchymal stem cells (MSC). Induction of AD in mouse MSC of the C3H10T1/2 cell line was associated with an
increase in the expression levels of BMI1, the genes of pRb family (RB, p130) and demethylase UTX, but not methyltransferase EZH2, whose products
regulate the methylation levels of H3K27. It was observed earlier that H3K27me3 may play the role of the epigenetic switch by promoting AD of human MSC via activating expression
of the PPARy2, the master gene of AD (Hemming et al., 2014). Here we show that inactivation of BMI1 using specific siRNA slows and decreases the levels of AD, but
does not abolish it. This is associated with a complete inhibition of the expression of adipogenic marker genes - PPARã2, ADIPOQ and a decrease in the expression of RB,
p130, but not UTX. The results obtained give evidence that the epigenetic mechanism regulating AD differentiation in mouse and human MSC is different.
Key words:
mesenchymal stem cells, adipocyte differentiation, Polycomb, Bmi1, pRb
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