Jmjd3 Inhibits Reprogramming by Upregulating Expression of INK4a/Arf and Targeting PHF20 for Ubiquitination

Abstract

Although somatic cell reprogramming to generate inducible pluripotent stem cells (iPSCs) is associated with profound epigenetic changes, the roles and mechanisms of epigenetic factors in this process remain poorly understood. Here we identify Jmjd3 as a potent negative regulator of reprogramming. Jmjd3-deficient MEFs produced significantly more iPSC colonies than did wild-type cells, while ectopic expression of Jmjd3 markedly inhibited reprogramming. We show that the inhibitory effects of Jmjd3 are produced through both histone demethylase-dependent and -independent pathways. The latter pathway is entirely novel and involves Jmjd3 targeting of PHF20 for ubiquitination and degradation via recruitment of an E3 ligase, Trim26. Importantly, PHF20-deficient MEFs could not be converted to fully reprogrammed iPSCs, even with knockdown of Jmjd3, Ink4a or p21, indicating that this protein exerts predominant effects on reprogramming. Our findings demonstrate a previously unrecognized role of Jmjd3 in cellular reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls this process.

Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex

“…Consistently, MOF was shown to catalyze p53 Lys120 acetylation, which is required for optimal transcription activation of p53 target genes (Sykes et al 2006;Li et al 2009), while the tudor domain of PHF20 associates with methylated Lys370 and Lys382 of p53 (Cui et al 2012). Both MOF and WDR5 are important regulators of the embryonic stem cell core transcription network (Ang et al 2011;Li et al 2012;Taylor et al 2013), and PHF20 is required for somatic cell reprogramming (Zhao et al 2013a). Despite the emerging global importance of the NSL complex in transcription regulation, the details and specificity of its recruitment to chromatin as well as its mode of action are currently poorly understood.…”

“…The subunits of the NSL complex play important roles in various cellular processes, including transcription regulation and stem cell identity maintenance or reprogramming (Raja et al 2010;Li et al 2012;Zhao et al 2013a), and are misregulated in various diseases, including cancer (Fraga et al 2005;Gupta et al 2008;Yoshida et al 2013). The composition of the NSL complex has been analyzed by mass spectrometry (Mendjan et al 2006;Cai et al 2010), but essentially nothing is known about its biochemistry, molecular structure, and mode of action.…”

The localization of histone H3K27me3 demethylase Jmjd3 is dynamically regulated

“…16,17 Interestingly, a recent study showed that Jmjd3 decreases the efficiency of the generation of iPSCs cells via Ink4a/Arf-dependent and -independent mechanisms. 18 These studies suggest that Jmjd3 functions as an epigenetic barrier for preventing tumorigenesis and ectopic transdifferentiation. Therefore, understanding the molecular controls that regulate Jmjd3 demethylase activity is crucial for the finding of novel treatments of cancer and the improvement of cellular engineering.…”

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…KDM6B (JMJD3), in contrast, is induced upon inflammation or exposure to viral or oncogenic stimuli [100,101]. It controls neuronal and epidermal differentiation and inhibits reprogramming [102]. In addition, both KDM6A and KDM6B have key roles in MSC lineage specification.…”