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The EZH1–SUZ12 Complex Positively Regulates the Transcription of NF-Κb

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The EZH1–SUZ12 Complex Positively Regulates the Transcription of NF-Κb © 2016. Published by The Company of Biologists Ltd | Journal of Cell Science (2016) 129, 2343-2353 doi:10.1242/jcs.185546 RESEARCH ARTICLE The EZH1–SUZ12 complex positively regulates the transcription of NF-κB target genes through interaction with UXT Shuai-Kun Su, Chun-Yuan Li, Pin-Ji Lei, Xiang Wang, Quan-Yi Zhao, Yang Cai, Zhen Wang, Lianyun Li* and Min Wu* ABSTRACT zeste 2 polycomb repressive complex 2 subunit (EZH2) (Shen et al., Drosophila Unlike other members of the polycomb group protein family, EZH1 2008). EZH2 mimics the function of E(Z) in and is the has been shown to positively associate with active transcription on a main methyltransferase for H3K27 in mammalian cells (Shen et al., genome-wide scale. However, the underlying mechanism for this 2008). However, controversial reports exist about EZH1, which behavior still remains elusive. Here, we report that EZH1 physically means its activities have been a puzzle for a long time. Compared interacts with UXT, a small chaperon-like transcription co-activator. with EZH2, EZH1 has lower enzymatic activity, suggesting it might UXT specifically interacts with EZH1 and SUZ12, but not EED. have distinct functions (Margueron et al., 2008). Several groups Similar to upon knockdown of UXT, knockdown of EZH1 or SUZ12 reported that EZH1 methylates histone H3K27 and compensates for through RNA interference in the cell impairs the transcriptional the functions of EZH2 upon its absence (Bae et al., 2015; Hidalgo activation of nuclear factor (NF)-κB target genes induced by TNFα. et al., 2012; Shen et al., 2008). Recently, Mousavi et al. have EZH1 deficiency also increases TNFα-induced cell death. reported that EZH1 behaves as a positive regulator for transcription Interestingly, chromatin immunoprecipitation and the following next- and is required for proper recruitment of RNA polymerase II (Pol II) generation sequencing analysis show that H3K27 mono-, di- and to target genes (Mousavi et al., 2012). Another study has tri-methylation on NF-κB target genes are not affected in EZH1-or demonstrated that EZH1 forms two different complexes with UXT-deficient cells. EZH1 also does not affect the translocation of the distinguished functions (Xu et al., 2015). One is similar to the p65 subunit of NF-κB (also known as RELA) from the cytosol to the classical PRC2 complex containing EZH1, embryonic ectoderm nucleus. Instead, EZH1 and SUZ12 regulate the recruitment of p65 development (EED) and SUZ12, and the second complex is only and RNA Pol II to target genes. Taken together, our study shows that with SUZ12 (Xu et al., 2015). The former complex inhibits EZH1 and SUZ12 act as positive regulators for NF-κB signaling and transcription, while the latter one activates transcription (Xu et al., demonstrates that EZH1, SUZ12 and UXT work synergistically to 2015). However, the detailed mechanisms of how the two EZH1 regulate pathway activation in the nucleus. complexes regulate transcription remain elusive. The nuclear factor κ-light-chain-enhancer of activated B cells KEY WORDS: EZH1, UXT, Histone methylation, Transcription (NF-κB) signaling pathway is a well-studied pathway involved regulation, NF-κB signaling pathway in inflammation, immunity and anti-apoptosis (Iwai, 2012; Oeckinghaus et al., 2011). It is activated upon many extracellular INTRODUCTION signals, and tumor necrosis factor (TNFα) has been used as one of The epigenetic control of chromatin is crucial for transcription the typical molecules to activate the pathway (Hu et al., 2014; Wang regulation and the proper response to extracellular signals in the cell. et al., 2012; Zhang et al., 2014). Although the regulations of NF-κB The polycomb repressive complexes 1 and 2 (PRC1 and PRC2) are pathway in the cytosol have been extensively studied, the events the most studied protein complexes among all the Polycomb group after NF-κB enters the nucleus are still not clear and have emerged (PcG) proteins and have long been considered as transcription as being crucial regulatory steps for pathway activation. Multiple repressors (Campos et al., 2014; Conway et al., 2015; Margueron and histone methyltransferases are involved in pathway regulation. We Reinberg, 2011). PRC1 inhibits transcription by regulating mono- have previously found that lysine (K)-specific methyltransferase ubiquitination on histone H2A, whereas PRC2 is responsible for the 2A (KMT2A; also known as MLL1), a histone H3K4 methylation on histone H3K27 (Margueron and Reinberg, 2011). methyltransferase, selectively regulates the activation of NF-κB In Drosophila, three major subunits form PRC2 complex, target genes (Wang et al., 2012). EZH2 regulates the activation of including Enhancer of zeste [E(z)], extra sexcombs (ESC) and NF-κB pathway by distinct mechanisms in different cell lines, suppressor of zeste 12 (SUZ12), among which E(Z) is the enzyme which shows the complexity of epigenetic regulators (Lee et al., for H3K27 methylation (Lanzuolo and Orlando, 2012). In 2011). The NF-κB molecule itself is also regulated by protein mammals, two close homologs exist for E(Z), enhancer of zeste 1 methylation. SET-domain-containing (lysine methyltransferase) 7 polycomb repressive complex 2 subunit (EZH1) and enhancer of (SET7; also known as SET9 and SETD7) methylates NF-κBat Lys314 and Lys315 and promotes NF-κB degradation (Yang et al., 2009). However, SET7 also methylates Lys37 on NF-κB and Department of Biochemistry and Molecular Biology, College of Life Sciences, selectively activates target genes (Ea and Baltimore, 2009). Besides Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, Hubei 430072, China. protein methylation, multiple transcription co-regulators have been found to be involved in the activation of NF-κB target genes. For *Authors for correspondence ([email protected]; [email protected]) example, the ubiquitously expressed prefoldin-like chaperone UXT M.W., 0000-0003-1372-4764 (also known as STAP1 and ART-27), a small chaperone-like protein, has been reported to interact with the p65 subunit of NF-κB Received 30 December 2015; Accepted 20 April 2016 (also known as RELA) and functions as a transcription co-activator, Journal of Cell Science 2343 RESEARCH ARTICLE Journal of Cell Science (2016) 129, 2343-2353 doi:10.1242/jcs.185546 as well as a cytoplasmic regulator for anti-viral pathway (Huang genes (Sun et al., 2007). Given that EZH1 interacts with UXT, we et al., 2011, 2012; Sun et al., 2007). However, how UXT contributes studied whether EZH1 also regulates the NF-κB pathway. UXT was to the activation of NF-κB target genes is still not clear. knocked down by small interfering RNA (siRNA) in the HCT116 In this study, we discovered that UXT physically interacts with cell, and the TNFα-induced expression of NFKBIA (also known as EZH1 and SUZ12, but not with EED or EZH2. EZH1 and UXT are IκBα), CXCL8 and TNFAIP3 (also known as A20), three typical required for p65 recruitment to NF-κB target genes and the NF-κB target genes, were significantly downregulated, as reported subsequent induction of expression. EZH1 and UXT are associated previously (Fig. 3A; Sun et al., 2007). Then, we knocked down with Pol II, and regulate its loading to chromatin. Our study EZH1 in HCT116 with two different siRNAs. Similar to upon UXT indicates that UXT, EZH1 and SUZ12 together help to link p65 with knockdown, the induction of the above three genes was greatly Pol II and regulate the activation of NF-κB target genes. impaired, indicating that EZH1 positively regulates the activation of NF-κB target genes (Fig. 3B). We also knocked down EZH1 in RESULTS RKO, HEK293 and U2OS cell lines, and observed the same results The physical interaction between EZH1 and UXT (Fig. S1A–C). To investigate whether EZH1 regulates the activation To investigate the role of EZH1 in regulating transcription, a yeast of NF-κB target genes during the anti-viral response, Sendai virus two-hybrid screen was performed with full-length EZH1 as the bait. (SeV) was used to treat HCT116, and we found that the expression Multiple clones were identified encoding the open reading frame of of NF-κB downstream genes was significantly impaired after EZH1 UXT, which has been shown to be a transcription co-factor and to knockdown (Fig. S1D). To further confirm the role of EZH1 in NF- interact with multiple transcription factors (Carter et al., 2014; Li κB signaling, we profiled the gene expression pattern after EZH1 et al., 2014; McGilvray et al., 2007; Sun et al., 2007). We speculated knockdown with next-generation sequencing. EZH1 deficiency that UXT might regulate transcription by bridging the master impaired the expression of almost all the TNFα-induced genes, transcription factors and epigenetic regulators and continued with similar to the effect of UXT (Fig. 3C), whereas EZH1 only regulated the following studies. the basal expression of a small portion of genes (Table S1). This is EZH1 UXT We cloned the full-length cDNA of and into different from some of the other epigenetic regulators, such as mammalian expression vectors, and performed immunoprecipitation KMT2A, which selectively regulates the activation of NF-κB target – with anti-FLAG or anti-HA antibodies. HA EZH1 successfully genes by modifying H3K4 methylation (Wang et al., 2012), – pulled down FLAG UXT and vice versa (Fig. 1A). To examine the suggesting that EZH1 might regulate NF-κB signaling through a interaction between endogenous proteins, we generated antibodies distinctive mechanism. against the two proteins and performed immunoprecipitation. The Interestingly, when analyzing the signaling pathway after UXT results showed that endogenous EZH1 and UXT are associated with knockdown, the differentially expressed genes were found to be each other (Fig. 1B). To further characterize whether EZH1 directly specifically enriched in the gene ontology terms ubiquitin-mediated interacts with UTX, both proteins were expressed in bacteria and proteolysis, cell cycle, p53 signaling etc, suggesting that UXT – purified with GST or His affinity resins.
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