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Kinetic and High-Throughput Profiling of Epigenetic Interactions by 3D

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Kinetic and High-Throughput Profiling of Epigenetic Interactions by 3D Kinetic and high-throughput profiling of epigenetic PNAS PLUS interactions by 3D-carbene chip-based surface plasmon resonance imaging technology Shuai Zhaoa,b,1, Mo Yangc,d,1, Wenfei Zhouc,d, Baichao Zhanga,b, Zhiqiang Chengc,d, Jiaxin Huanga,b, Min Zhanga,b, Zhiyou Wangc,d, Rui Wangc,d, Zhonglei Chena,b, Jinsong Zhuc,d,2, and Haitao Lia,b,2 aMinistry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; bTsinghua–Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; cChinese Academy of Sciences Center for Excellence in Nanoscience, Chinese Academy of Sciences Key Laboratory of Nanosystem and Hierarchical Fabrication, National Center for Nanoscience and Technology, Beijing 100190, China; and dUniversity of Chinese Academy of Sciences, Beijing 100049, China Edited by Shawn Li, Western University, London, ON, Canada, and accepted by Editorial Board Member Douglas Koshland July 17, 2017 (received for review March 14, 2017) Chemical modifications on histones and DNA/RNA constitute a tion of Ser-10 on H3 (H3S10ph) completely abrogates the binding of fundamental mechanism for epigenetic regulation. These modifi- H3 Lys-9 trimethylation (H3K9me3) by HP1 protein (9, 10). BRDT cations often function as docking marks to recruit or stabilize protein binds neither histone H4 Lys-5 acetylation (H4K5ac) nor cognate “reader” proteins. So far, a platform for quantitative and Lys-8 acetylation (H4K8ac) but engages H4 peptide bearing both high-throughput profiling of the epigenetic interactome is ur- marks with decent affinity (KD = 22 μM)(11).Insum,amorere- gently needed but still lacking. Here, we report a 3D-carbene chip- alistic and holistic understanding of how reader proteins engage based surface plasmon resonance imaging (SPRi) technology for this chromatin necessitates screening known and potential readers against purpose. The 3D-carbene chip is suitable for immobilizing versatile an exhaustive collection of histone PTMs and relevant combinations biomolecules (e.g., peptides, antibody, DNA/RNA) and features low thereof, ideally in a high-throughput and quantitative manner. nonspecific binding, random yet function-retaining immobilization, However, to the best of our knowledge, such a demand has not been and robustness for reuses. We systematically profiled binding kinetics addressed by the epigenetic field. of 1,000 histone “reader–mark” pairs on a single 3D-carbene chip and As an advanced optical-based quantitative detection method, validated two recognition events by calorimetric and structural stud- surface plasmon resonance (SPR) sensing has been extended to the ies. Notably, a discovery on H3K4me3 recognition by the DNA mis- SPR microscopy or imaging (SPRi) technology for high-throughput Capsella rubella match repair protein MSH6 in suggests a mechanism probing of biomolecular interactions (12, 13). Despite some in- of H3K4me3-mediated DNA damage repair in plant. trinsic disadvantages of SPR, such as influence of immobilization and surface fouling, SPRi stands out as a powerful detection tool as SPR imaging | epigenetic interactions | histone modifications | it probes analyte label-freely and measures binding kinetics in real BIOCHEMISTRY nucleic acid modifications | 3D-carbene chip Significance espite having identical genetic information, human cells differentiate into different identities during development. D In the era of functional proteomics, a myriad of new interactions, The mechanisms leading to differential transcriptional and de- notably those modification-dependent ones, are widely suggested velopmental outcomes under the same genetic background are by advanced proteomic approaches and bioinformatic analysis. known as epigenetics. Posttranslational modification (PTM) on Therefore, there exists an urgent need to develop a technology histones is a major epigenetic regulatory mechanism such that for high-throughput mapping and quantitative characterization of more than 30 types of PTMs occur on histones, with new ones biomolecular binding events. This study achieved the immobili- still being discovered (1). The well-studied histone PTMs include zation and kinetic detection of various biomacromolecules (in- methylation, acetylation, phosphorylation, and most recently cluding modified peptides and modified nucleic acids) in high discovered nonacetyl acylations (2). Histone PTMs regulate throughput through the 3D-carbene chip-based surface plasmon transcription either by directly affecting the structure/stability of resonance imaging (SPRi) technology. Modified histone peptides single nucleosome and the high-order folding of chromatin, or by and nucleic acids, which are key epigenetic marks, could be effi- recruiting specific effector proteins (also called histone readers) ciently probed by this platform. We envision that the 3D-carbene recognizing them (3, 4). SPRi technology described here will have wide appeal in profiling The ever-expanding repertoire of histone readers are diverse and discovering biological recognitions in and beyond epigenetics. in sequence and structure, and how they engage diversely mod- ified chromatin is complicated, hard to predict, yet important for Author contributions: H.L. and J.Z. conceived research; H.L. and J.Z. designed research; S.Z. their functions. Often one type of reader domains can recognize and M.Y. designed and performed experiments with help from W.Z., B.Z., Z. Cheng., J.H., different types of PTMs. For example, PHD finger proteins can M.Z., Z.W., R.W., and Z. Chen; H.L., J.Z., S.Z., and M.Y. analyzed data; and H.L., J.Z., S.Z., recognize unmodified, methylated, or acylated lysine residue on and M.Y. wrote the paper. histones (5, 6). Several YEATS domain proteins, originally The authors declare no conflict of interest. identified as readers of lysine acetylation (Kac), in fact accom- This article is a PNAS Direct Submission. S.L. is a guest editor invited by the Editorial Board. modate a wide range of lysine acylations with lysine crotonyla- Freely available online through the PNAS open access option. tion (Kcr) most preferred (7). These “mark–reader” interactions Data deposition: The atomic coordinates and structure factors have been deposited in the – vary greatly in binding affinity, ranging from submicromolar to mil- Protein Data Bank, www.wwpdb.org (PDB ID codes 5WXG [TAF3PHD H3(1–15)K4ac com- plex] and 5WXH [TAF3PHD–H3(1–15)K4me3 complex]). limolar levels. To complicate the matter further, the recognition of 1S.Z. and M.Y. contributed equally to this work. marksbyreaderproteinsisofteneithersynergizedorantagonizedby 2To whom correspondence may be addressed. Email: [email protected] or jizhu@ other marks in close proximity (8). For instance, Spindlin1 recognizes nanoctr.cn. histone H3 trimethylation of Lys-4 (H3K4me3) and asymmetrically This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. dimethylation of Arg-8 (H3R8me2a) in concert, while phosphoryla- 1073/pnas.1704155114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1704155114 PNAS | Published online August 14, 2017 | E7245–E7254 Downloaded by guest on September 26, 2021 time and in microarray format. The immobilization strategy and the subjected the chip to interaction profiling of eight histone reader spacing of ligands on the chip surface can influence the detecting proteins. The positive and negative controls set in the experi- efficiency of SPRi. Carbene-based cross-linking strategy, which ments matched well with known results. We demonstrated that rapidly immobilizes molecules in random orientation due to its high 3D-carbene–based SPRi technology was suitable to kinetically and diverse chemical reactivity (e.g., carbon insertion, Michael ad- analyze epigenetic interactions in high throughput. We confirmed a dition, nucleophilic reaction, etc.), is becoming an optimized strong interaction between TAF3–H3K4me3 and validated a immobilization method for microarray fabrications (14–16). unique weak interaction between TAF3–H3K4ac by isothermal ti- Meanwhile, due to its high loading capacity for biomolecules and tration calorimetry (ITC) and crystallography. Importantly, an epi- antifouling properties, 3D polymer surface with a designed structure genetic interaction between H3K4me3 and the tudor domain of often shows high signal-to-noise ratio in SPRi (17–19). Theoreti- mutS homolog 6 (MSH6) in Capsella rubella was discovered, sug- cally, a carbene-based 3D surface could immobilize biomolecules gesting a role of H3K4me3 in DNA mismatch repair in plant. randomly in position and orientation to best retain the functionality Collectively, these results demonstrate that the 3D-carbene SPRi and, in the meantime, has the advantage of high sensitivity and low technology is suitable for kinetic and high-throughput analysis of the nonspecific adsorption. However, binding detection of randomly epigenetic “readership” and for interaction discovery. immobilized biomolecules by the 3D-carbene SPRi technology has yet to be explored systematically. Results Here, we report the quantitative and high-throughput profiling Design and Fabrication of the 3D-Carbene Chip. The 3D-carbene of epigenetic interactions by the 3D-carbene chip-based SPRi SPRi technology was designed as in Fig. 1A. As the core element technology. We demonstrated that the 3D-carbene chip could of the chip, a 3D-carbene surface was constructed
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