Human KDM6B peptide

Cellular senescence is defined by an irreversible growth arrest and is an important biological mechanism for suppression of tumor formation. Although deletion/mutation to DNA sequences is one mechanism by which cancer cells can escape senescence, little is known about the epigenetic factors contributing to this process. Histone modifications and chromatin remodeling related to the function of a histone demethylase, jumonji domain containing protein 3 (JMJD3; also known as KDM6B), play an important role in development, tissue regeneration, stem cells, inflammation, and cellular senescence and aging. The role of JMJD3 in cancer is poorly understood and its function may be at the intersection of many pathways promoted in a dysfunctional manner such as activation of the senescence-associated secretory phenotype (SASP) observed in aging. (C) 2016 Elsevier B.V. All rights reserved.

Long noncoding RNAs (LncRNAs) have been implicated in the regulation of adipocyte and osteoblast differentiation. However, the functional contributions of LncRNAs to adipocyte or osteoblast differentiation remain largely unexplored. In the current study we have identified a novel LncRNA named peroxisome proliferator-activated receptor gamma coactivator-1 beta-OT1 (PGC1 beta-OT1). The expression levels of PGC1 beta-OT1 were altered during adipogenic and osteogenic differentiation from progenitor cells. 5'- and 3'-rapid amplification of cDNA ends (RACE) revealed that PGC1 beta-OT1 is 1759 nt in full length. Overexpression of PGC1 beta-OT1 in progenitor cells inhibited adipogenic differentiation, whereas silencing of endogenous PGC1 beta-OT1 induced adipogenic differentiation. By contrast, overexpression of PGC1 beta-OT1 in progenitor cells stimulated, whereas silencing of PGC1 beta-OT1 inhibited osteogenic differentiation. In vivo experiment showed that silencing of endogenous PGC1 beta-OT1 in marrow stimulated fat accumulation and decreased osteoblast differentiation in mice. Mechanism investigations revealed that PGC1 beta-OT1 contains a functional miR-148a-3p binding site. Overexpression of the mutant PGC1 beta-OT1 with mutation at the binding site failed to regulate either adipogenic or osteogenic differentiation. In vivo crosslinking combined with affinity purification studies demonstrated that PGC1 beta-OT1 physically associated with miR148a-3p through the functional miR-148a-3p binding site. Furthermore, PGC1 beta-OT1 affected the expression of endogenous miR-148a-3p and its target gene lysine-specific demethylase 6b (KDM6B). Supplementation of miR-148a-3p in progenitor cells blocked the inhibitory effect of PGC1 beta-OT1 on adipocyte formation. Moreover, overexpression of Kdm6b restored the osteoblast differentiation which was inhibited by silencing of endogenous PGC1 beta-OT. Our studies provide evidences that the novel LncRNA PGC1 beta-OT1 reciprocally regulates adipogenic and osteogenic differentiation through antagonizing miR-148a-3p and enhancing KDM6B effect.