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Sumoylated Non-Canonical Polycomb PRC1.6 Complex As a Prerequisite

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Sumoylated Non-Canonical Polycomb PRC1.6 Complex As a Prerequisite Sotomska et al. Epigenetics & Chromatin (2021) 14:38 https://doi.org/10.1186/s13072-021-00412-9 Epigenetics & Chromatin RESEARCH Open Access SUMOylated non-canonical polycomb PRC1.6 complex as a prerequisite for recruitment of transcription factor RBPJ Małgorzata Sotomska1, Robert Liefke2,3, Francesca Ferrante1, Heiko Schwederski4, Franz Oswald4 and Tilman Borggrefe1* Abstract Background: Notch signaling controls cell fate decisions in many contexts during development and adult stem cell homeostasis and, when dysregulated, leads to carcinogenesis. The central transcription factor RBPJ assembles the Notch coactivator complex in the presence of Notch signaling, and represses Notch target gene expression in its absence. Results: We identifed L3MBTL2 and additional members of the non-canonical polycomb repressive PRC1.6 complex in DNA-bound RBPJ associated complexes and demonstrate that L3MBTL2 directly interacts with RBPJ. Depletion of RBPJ does not afect occupancy of PRC1.6 components at Notch target genes. Conversely, absence of L3MBTL2 reduces RBPJ occupancy at enhancers of Notch target genes. Since L3MBTL2 and additional members of the PRC1.6 are known to be SUMOylated, we investigated whether RBPJ uses SUMO-moieties as contact points. Indeed, we found that RBPJ binds to SUMO2/3 and that this interaction depends on a defned SUMO-interaction motif. Furthermore, we show that pharmacological inhibition of SUMOylation reduces RBPJ occupancy at Notch target genes. Conclusions: We propose that the PRC1.6 complex and its conjugated SUMO-modifcations provide a favorable environment for binding of RBPJ to Notch target genes. Keywords: Notch signaling, Polycomb repressive complex, RBPJ, Sumoylation, Epigenetics Background absence of a Notch signal, RBPJ assembles an HDAC- Notch signal transduction is an evolutionary conserved containing corepressor complex and represses tran- pathway that regulates stem cell maintenance and difer- scription. Te Notch transcriptional signature is quite entiation decisions throughout development. Dysregula- diverse in diferent tissues and cell types, even in related tion of either NOTCH receptors or their modifers are cell types, such as B- and T-cells. Transcription factor in linked to carcinogenesis [1–3]. At the molecular level, concert with chromatin modifers establish a chromatin ligand binding leads to the proteolytic processing of the environment that predetermines specifcity of the Notch Notch receptor. Its intracellular domain migrates then target gene expression [3–5]. In regard to posttransla- into the nucleus, associates with the transcription factor tional modifcations (PTMs), not only histone tails, but RBPJ and activates transcription of target genes. In the also the Notch coactivator complex are known to be phosphorylated, methylated, acetylated, SUMOylated *Correspondence: [email protected] and ubiquitinylated [6–8]. Tese modifcations control 1 Institute of Biochemistry, Justus-Liebig University of Giessen, not only the stability of Notch, but also determine ampli- Friedrichstrasse 24, 35392 Giessen, Germany tude and duration of the Notch response [9] and can be Full list of author information is available at the end of the article incorporated upon cellular stress signals [10]. © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sotomska et al. Epigenetics & Chromatin (2021) 14:38 Page 2 of 15 Te central player controlling the expression of Here, we show that components of the PRC1.6 com- Notch target genes is the transcription factor RBPJ, plex together with multiple SUMO-modifcations physi- also known as CBF1 (C promoter binding factor) or cally interact with the transcription factor RBPJ, thereby CSL (Homo sapiens CBF1, Drosophila melanogaster supporting its binding to enhancers of Notch target Suppressor of Hairless, and Caenorhabditis elegans genes. Specifcally, we found that L3MBTL2 and E2F6 Lag-1). RBPJ binds to the sequence 5′-CGT GGG AA-3′ are required for efcient RBPJ binding. Furthermore, we [11] and its genome-wide distribution has been studied reveal that RBPJ utilizes its SUMO interaction motif as in several tissues [12]. In the absence of a Notch sig- additional docking site and provide evidence that high nal, RBPJ assembles a corepressor complex containing local SUMO levels and occupancy of the PRC1.6 complex NCoR/HDACs [13] and histone demethylases, such as are favorable for RBPJ binding. KDM1A/LSD1 [14]. Polycomb group proteins assemble in two major repres- Results sive multi-subunit complexes known as PRC1 (Polycomb DNA‑bound RBPJ is associated with several PRC1.6 repressive complex 1) and PRC2. PRC1 and PRC2 difer components in their enzymatic activities and function. PRC1 con- To biochemically isolate RBPJ-containing complexes, tains the E3 ligase RING1/2 and PRC2 the repressing we took advantage of a DNA double-stranded oligonu- histone methyltransferase EZH2. Te PRC1-components cleotide containing two RBPJ binding sites 5′-GTG GGA relevant for this study (L3MBTL2, MGA and E2F6) are A-3’ (Fig. 1a), which allows the formation of DNA-bound subunits of the PRC1.6 complex described by Trojer [15]. dimeric RBPJ complexes [27]. We speculated that DNA- PRC1.6 belongs to the group of non-canonical PRC1, binding of RBPJ may stabilize the complex and in addi- which are known to be recruited also in an H3K27me3- tion prevent unspecifc binding of proteins to the charged independent manner [16, 17]. Te genome-wide distri- DNA-binding region of RBPJ, similar to the previously bution of PRC1.6 has been studied using CRISPR-Cas9 described trapping method [28]. depletion of the individual components L3MBTL2, E2F6, Nuclear extracts from HeLa cells expressing FLAG- MGA and PCGF6 combined with ChIP-Seq analyses of HA-tagged RBPJ (Fig. 1b) were generated by salt extrac- the same proteins, revealing that binding of PRC1.6 com- tion. Subsequently, we added the double-stranded ponents overlap genome-wide and that L3MBTL2 and oligonucleotide prior to dialysis. To prevent binding of E2F6 contribute to chromatin binding of the PRC1.6 unspecifc DNA binding proteins to the RBPJ-bound complex [18]. In addition, SUMOylation of L3MBTL2 DNA, we additionally added a mutated oligonucleotide is required for transcriptional repression of endogenous (Fig. 1a) in excess. In a control experiment, we did not target genes [19]. add any DNA to the samples. After the dialysis step, we SUMO (small ubiquitin-like modifer) is a 11 kDa pro- isolated the complexes using Flag-beads (Fig. 1c). When tein that modifes its target proteins through covalent analysing the bound proteins by silver staining, we found binding to lysine residues [20]. Te family of SUMO that adding the oligonucleotide (wild type and mutated proteins consists of three evolutionary conserved, func- for the RBPJ binding motif) strongly reduced the level of tional isoforms (SUMO1, SUMO2 and SUMO3) of which unspecifc proteins (Fig. 1d). In particular, the amount the last two are 97% identical and are, therefore, often of histone proteins was strongly reduced in the DNA- referred to as SUMO2/3 [21]. SUMO is attached to pro- treated sample as compared with the untreated sample teins using E1 (Aos1/Uba2), E2 (Ubc9), and several E3 (Fig. 1d). Subsequently, the obtained protein samples ligase enzymes. Tere are also proteins that bind SUMO were subjected to mass-spectrometric analysis. Te MS non-covalently by specifc SUMO interacting motifs data confrmed the strong reduction of histone proteins (SIMs), implicating that SUMO and SIM-containing and chromatin-associated proteins in the DNA-bound proteins can form multiprotein networks [22]. In conse- RBPJ sample (Fig. 1e, Additional fle 1: Table S1). Of note, quence, SUMO modifcations are not only regulating the RBPJ itself, and known RBPJ interactors either were not functions of individual proteins, but also regulate protein afected by adding the DNA or we obtained even higher complex assembly and recruitment [23–25]. Importantly, peptide numbers (Fig. 1f). Tus, by adding the RBPJ- Cossec and colleagues revealed that chromatin-bound binding oligonucleotide during the RBPJ complex puri- SUMO and the PRC1.6 complex, in particular L3MBTL2, fcation procedure, we substantially improved the signal are found at the overlapping genomic sites. It is reported to noise ratio. Closer inspection of the data showed that that multiple SUMO-moieties act as a “glue” for both we could identify many known RBPJ corepressor and transcription factors and chromatin
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