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A Prelude to the Proximity Interaction Mapping of CXXC5

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A Prelude to the Proximity Interaction Mapping of CXXC5 www.nature.com/scientificreports OPEN A prelude to the proximity interaction mapping of CXXC5 Gamze Ayaz1,4,6*, Gizem Turan1,6, Çağla Ece Olgun1,6, Gizem Kars1, Burcu Karakaya1, Kerim Yavuz1, Öykü Deniz Demiralay1, Tolga Can2, Mesut Muyan1,3* & Pelin Yaşar1,5,6 CXXC5 is a member of the zinc-fnger CXXC family proteins that interact with unmodifed CpG dinucleotides through a conserved ZF-CXXC domain. CXXC5 is involved in the modulation of gene expressions that lead to alterations in diverse cellular events. However, the underlying mechanism of CXXC5-modulated gene expressions remains unclear. Proteins perform their functions in a network of proteins whose identities and amounts change spatiotemporally in response to various stimuli in a lineage-specifc manner. Since CXXC5 lacks an intrinsic transcription regulatory function or enzymatic activity but is a DNA binder, CXXC5 by interacting with proteins could act as a scafold to establish a chromatin state restrictive or permissive for transcription. To initially address this, we utilized the proximity-dependent biotinylation approach. Proximity interaction partners of CXXC5 include DNA and chromatin modifers, transcription factors/co-regulators, and RNA processors. Of these, CXXC5 through its CXXC domain interacted with EMD, MAZ, and MeCP2. Furthermore, an interplay between CXXC5 and MeCP2 was critical for a subset of CXXC5 target gene expressions. It appears that CXXC5 may act as a nucleation factor in modulating gene expressions. Providing a prelude for CXXC5 actions, our results could also contribute to a better understanding of CXXC5-mediated cellular processes in physiology and pathophysiology. Te methylation of mammalian genomic DNA, which predominantly arises post-replicatively at the 5’ posi- tion of the cytosine base in the context of CpG dinucleotides, varies across cell types, developmental stages, physiological and pathophysiological conditions 1. Acting as stable and heritable epigenetic marks, methylated CpGs present in 80% of CpGs in the genome and involve both genic and intergenic regions2. Methylated CpGs are specifcally recognized and bound by methyl-CpG-binding proteins, which in turn generate a chromatin environment refractory to transcription by recruiting a variety of chromatin modifers 3,4. Although the majority of CpGs are methylated, about 70% of annotated human gene promoters are associ- ated with unmethylated DNA stretches called CpG islands (CGIs), which are rich in C and G nucleotides with a high density of CpG dinucleotides 5,6. Te structurally and functionally distinct zinc-fnger (ZF)-CXXC family proteins interact with unmodifed CpG dinucleotides through a highly conserved ZF-CXXC domain character- ized by two consecutive cysteine-rich motifs (CXXCXXC) that associate with two Zn ++ ions forming zinc-fnger structures. Upon binding to unmethylated CpG motifs with varying afnities and specifes within the context of surrounding base composition7, the ZF-CXXC family proteins establish a chromatin architecture directly through chromatin-modifying enzymatic activities and/or indirectly through the recruitment of chromatin-modifers to modulate gene expressions4,8,9. CXXC5, also known as RINF (Retinoid-Inducible Nuclear Factor) and WID (WT1-Induced Inhibitor of Dishevelled), is a member of the ZF-CXXC family. CXXC5 is located on chromosome 5q31.2 and encodes a 322 amino-acid protein with a predicted molecular mass of 33 kDa8,10. Retinoic acid11, transforming growth factor-β12, bone morphogenetic protein 413,14, Wnt3a15–17, and estrogen18–21 modulate the expression of CXXC5 in experimental systems. Te encoded CXXC5 protein alters gene expressions 13,17,21–27 that result in the modula- tion of diverse cellular events, including signal transduction, DNA damage response, metabolism, proliferation, diferentiation, and death11–13,15,21,22,24,25,27–30. 1Department of Biological Sciences, Middle East Technical University, 06800 Ankara, Turkey. 2Department of Computer Engineering Middle, East Technical University, 06800 Ankara, Turkey. 3Cansyl Laboratories, Middle East Technical University, 06800 Ankara, Turkey. 4Present address: Cancer and Stem Cell Epigenetics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. 5Present address: Epigenetics and Stem Cell Biology Laboratory, Single Cell Dynamics Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. 6These authors contributed equally: Gamze Ayaz, Gizem Turan, Çağla Ece Olgun and Pelin Yaşar. *email: [email protected]; [email protected] Scientifc Reports | (2021) 11:17587 | https://doi.org/10.1038/s41598-021-97060-6 1 Vol.:(0123456789) www.nature.com/scientificreports/ However, the underlying mechanism by which CXXC5 regulates gene expressions remains unclear. We recently showed that CXXC5 is an unmethylated CpG binder but lacks an intrinsic transcription regulatory function21. Tis raises the possibility that CXXC5 acts as a nucleation factor to establish a transcription state restrictive or permissive for transcription by interacting with transcription factors, transcription co-regulatory proteins, histone, and/or DNA modifers. Consistent with this prediction, CXXC5 appears to be involved in epigenetic alterations, including CpG methylations and histone modifcations by recruiting TET2 (the ten-eleven translocation methylcytosine dioxygenase 2) at a subset of CGI promoters that results in the modulation of gene expression in plasmacytoid dendritic cells23. Similarly, CXXC5 was recently shown to infuence the establishment and maintenance of DNA methylation 22 as well as hydroxymethylation in embryonic stem cells 22 and immature erythroid cells27. It appears that CXXC5 regulates the transcription of TET1 and TET2 and interacts with TET1 and TET2 to modulate the expression of pluripotency genes, including Nanog and Oct4 (Octamer-Binding Pro- tein 4)22. Nanog and Oct4, in turn, cooperate with CXXC5 as the protein partner at a subset of gene promoters and enhancers to modulate the expression of genes involved in the facilitation of diferentiation22. Likewise, it was recently reported that the enhanced synthesis and interaction of CXXC5 with TET2 could pose challenges for the treatment of castration-resistant prostate cancer by increasing the accessibility of non-canonical DNA binding sites for androgen receptor 31. Moreover, the interaction of CXXC5 with TET2 could afect the stability of TET232. It was also reported that CXXC5 inhibits the expression of CD40L (CD40 ligand gene) by interacting with histone-lysine N-methyltransferase SUV39H1 (KMT1A) at the gene promoter 26. Furthermore, CXXC5 was reported to interact with FOXL2 (Forkhead Box L2)33, RBPJ (Recombination Signal Binding Protein For Immunoglobulin Kappa J Region)24, Sall4 (Spalt Like Transcription Factor 4)34,35, members of SMAD (Mothers against decapentaplegic homolog) family29,36, and VDR (Vitamin D receptor)30 to modulate gene expressions. Additionally, CXXC5 was shown to serve as a negative feedback regulator of the Wnt/β-catenin signaling pathway by interacting with the Dvl (Dishevelled) protein in the cytoplasm of dermal fbroblast 14–16,37. Since proteins perform their functions in a network of proteins whose identities and amounts change tempo- rally and spatially in response to intrinsic and extrinsic stimuli in a lineage-specifc manner, the identifcation of protein partners of CXXC5 would critically contribute to a better understanding of the mechanisms of CXXC5- mediated cellular processes in physiology and pathophysiology. Following its introduction, the proximity- dependent biotinylation approach (BioID) has been efectively used for the identifcation of interacting partners of many proteins38,39. BioID is based on the genetic fusion of a mutant E. coli biotin ligase enzyme, BirA*(R118G), which is defective in both self-association and DNA binding, to a protein-of-interest to biotinylate proximity proteins40,41. Biotinylated proteins are then selectively isolated with biotin-afnity capture and identifed with mass spectrometry (MS). Using the BioID-MS approach, we found that CXXC5 interacts with a large number of proteins mainly grouped in the regulation of gene expression which further clustered into proteins involved in DNA, chromatin, and RNA modifcations. Of the proteins, we selectively verifed that CXXC5 through its CXXC domain interacts with EMD (Emerin), MAZ (MYC Associated Zinc Finger Protein), and MeCP2 (Methyl-CpG Binding Protein 2). We also found that an interplay between CXXC5 and MeCP2 contributes to the expression of some of the CXXC5 target genes. Since CXXC5 lacks an intrinsic transcription regulatory function and enzy- matic activity but is an unmethylated CpG binder, our results, together with others, imply that CXXC5 may act as a nucleation factor/molecular scafold for gene expressions. Results Expression of the CXXC5-BirA* fusion protein in MCF7 cells. Although the underlying mechanism(s) is unclear, CXXC5 as a CpG dinucleotide binder is involved in gene expressions. Since the dynamically changing network of protein environment is a critical determinant for proteins to perform their functions in a cell- and signaling pathway-dependent manner, the identifcation of interacting partners of CXXC5 could provide criti- cal information about the mechanisms of target gene expressions. To begin to address this issue, we utilized the BioID-MS approach. To generate the protein
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