Evidence demonstrating the interplay between hypoxia

Evidence demonstrating the interplay between hypoxia and the dynamics of histone methylation is mounting [15], [43]. For example, hypoxia leads to an increase in H3K4me3 by inhibiting their responsible demethylase [44]. Hypoxia also leads to an increase in H3K9me2 by upregulating the methyltransferase G9a [45]. Our data show that PHF8 has distinct effects on H3K9me2 and H3K27me2, and that the outcome for each is gene-dependent. However, PHF8 appears to maintain H3K4me3 levels on even genes that are not bound by PHF8, suggesting that PHF8 may both positively regulate H3K4me3 methyltransferase and indirectly inhibit H3K4me3 demethylase. Genome-wide RNA-seq studies are required to reveal these mechanisms. Regardless of the details however, it is clear that the role of PHF8 in sustaining H3K4me3 is critical for hypoxia signaling, because HIF1α preferentially targets and regulates genes with H3K4me3 [29]. It remains puzzling how hypoxia regulates PHF8. Our data do not support the previously reported mechanism involving transcriptional regulation [18] and other studies show that HIF1α does not bind to the PHF8 promoter [46], [47]. It is possible that hypoxia signaling regulates PHF8 through post-translational mechanisms. USP7 counteracts the ubiquitination to stabilize PHF8 in breast cancer cells, in return, PHF8 transcriptionally regulates USP7, forming a regulatory feedback loop [38]. Hypoxia upregulates USP7 in glioma NKH 477 synthesis [48]. Thus, hypoxia could regulate PHF8 through USP7. Beyond, USP7 deubiquitinates and stabilizes HIF1α, PHF8 could regulate HIF1α through USP7 [49]. These hypotheses need to be tested in prostate cancer cells.
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Introduction Patients with intellectual disability (ID) show an impaired ability to reason, learn, and solve problems and are defined by a score of less than 70 in an IQ test. Mutations in over 400 genes have been implicated in ID, although the underlying molecular links between genotype and phenotype for most of these genes remain unknown (Oortveld et al., 2013). Proteins that bind, remodel, or modify chromatin play key roles during development, and their dysfunction is linked to many diseases, including neurodevelopmental disorders like ID (Johansson et al., 2014). We focus here on one chromatin modifier, KDM5, that is essential for cognition in mammals and acts by binding to, and enzymatically altering, the tail region of histone H3. Mammals encode four KDM5 paralogs, KDM5A, KDM5B, KDM5C, and KDM5D, while organisms with smaller genomes such as Drosophila and C. elegans encode a single KDM5 protein. KDM5 family proteins share a similar domain structure that allows them to influence gene expression through several distinct mechanisms. The Jumonji C (JmjC) domain is the enzymatic core of KDM5 proteins, and its only known role is to demethylate histone H3 that is trimethylated at lysine 4 (H3K4me3) (Klose and Zhang, 2007). In addition to removing H3K4me3, KDM5 proteins have two other domains that recognize the methylation status of H3K4. The C-terminal PHD motif binds to H3K4me2/3 and the N-terminal PHD recognizes histone H3 that is unmethylated at lysine 4 (H3K4me0) (Li et al., 2010, Torres et al., 2015, Wang et al., 2009). In addition to chromatin-based activities, KDM5 can also bind DNA in vitro through its A/T-rich interaction domain (ARID) (Tu et al., 2008, Yao et al., 2010). In all organisms examined, KDM5 proteins bind predominantly to promoter regions surrounding the transcriptional start site (TSS) (Iwase et al., 2016, Liu and Secombe, 2015, Lopez-Bigas et al., 2008, Xie et al., 2011). One means by which KDM5 proteins find their target genes is through interactions with sequence-specific transcription factors, including E2F, Myc, Foxo, and the Su(H) complex that acts downstream of Notch signaling (Liefke et al., 2010, Liu et al., 2014, Secombe et al., 2007, van Oevelen et al., 2008). Once at a promoter, KDM5 can affect transcription by demethylating promoter H3K4me3, which is a hallmark of transcriptionally active genes (Johansson et al., 2014). This activity is therefore primarily thought of as repressing target gene expression, a prediction that holds true for some KDM5 targets (Christensen et al., 2007). KDM5 proteins can also repress or activate transcription by demethylase-independent mechanisms. For example, KDM5 proteins can interact with the NuRD chromatin remodeling and sin3A/HDAC histone deacetylase complexes that impact transcription by altering nucleosome positioning and histone acetylation mechanisms, respectively (Barrett et al., 2007, Gajan et al., 2016, Lee et al., 2007, Lee et al., 2009, Nishibuchi et al., 2014).