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Histone H3 Tail Binds a Unique Sensing Pocket in EZH2 to Activate the PRC2 Methyltransferase

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Histone H3 Tail Binds a Unique Sensing Pocket in EZH2 to Activate the PRC2 Methyltransferase Histone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase Krupa S. Jania, Siddhant U. Jainb,c, Eva J. Gea, Katharine L. Diehla, Stefan M. Lundgrenb,c, Manuel M. Müllera,1, Peter W. Lewisb,c, and Tom W. Muira,2 aDepartment of Chemistry, Princeton University, Princeton, NJ 08544; bWisconsin Institute of Discovery, University of Wisconsin, Madison, WI 53715; and cDepartment of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715 Edited by Robert E. Kingston, Massachusetts General Hospital, Harvard Medical School, Boston, MA, and approved March 18, 2019 (received for review November 5, 2018) Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of subunit of PRC2, have been identified in hematologic malignancies, Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes lymphomas, myeloproliferative neoplasms, and myelodysplastic monomethylation, dimethylation, and trimethylation of lysine 27 syndromes (15). NSD1 mutations have been identified in pediatric on histone H3 (H3K27). Trimethylation at H3K27 (H3K27me3) is acute myelogenous leukemia, neuroblastoma, gliomas, and carci- associated with transcriptional silencing of developmentally im- nomas of the gastrointestinal tract, as well as head and neck cancers portant genes. Intriguingly, H3K27me3 is mutually exclusive with (7, 16, 17) and SETD2 mutations in clear cell renal cell carcinomas H3K36 trimethylation on the same histone tail. Disruptions in this (18). PRC2 mutations have also been described in patients with cross-talk result in aberrant H3K27/H3K36 methylation patterns Weaver syndrome (19, 20), while NSD1 loss of function has been and altered transcriptional profiles that have been implicated in identified in patients with Sotos syndrome (21). Further under- scoring the importance of an H3K27/H3K36 methylation balance, tumorigenesis and other disease states. Despite their importance, lysine-to-methionine mutations at these positions lead to epigenetic the molecular details of how PRC2 “senses” H3K36 methylation are cis dysregulation that is thought to drive the progression of rare pedi- unclear. We demonstrate that PRC2 is activated in by the un- atric cancers (11, 12, 17, 22–25). modified side chain of H3K36, and that this activation results in a PRC2 is a large molecular machine whose HMT activity is k fivefold increase in the cat of its enzymatic activity catalyzing tuned by a variety of inputs associated with the local chromatin H3K27 methylation compared with activity on a substrate methyl- environment (26, 27). The minimal active version of the enzyme BIOCHEMISTRY ated at H3K36. Using a photo-cross-linking MS strategy and his- comprises EZH2 as well as three other proteins: EED, SUZ12, tone methyltransferase activity assays on PRC2 mutants, we find and RbAp46/48 (28). The core architecture of PRC2 is impor- that EZH2 contains a specific sensing pocket for the H3K36 meth- tant for sensing the chromatin state. Catalytic stimulation of the ylation state that allows the complex to distinguish between mod- complex is carried out via a positive feedback mechanism ified and unmodified H3K36 residues, altering enzymatic activity through the binding of EED to H3K27me3 on a neighboring accordingly to preferentially methylate the unmodified nucleo- nucleosome (29, 30). This acts to boost PRC2 activity locally some substrate. We also present evidence that this process may within heterochromatic regions, leading to so-called “spreading” be disrupted in some cases of Weaver syndrome. (29). The core PRC2 complex is further elaborated by a series of ancillary subunits that have various roles in regulating enzyme PRC2 methyltransferase | designer chromatin | chemical biology activity in time and space (31, 32). For example, the JARID2 NA is packaged in the eukaryotic cell nucleus in one of two Significance Dgeneral chromatin states: transcriptionally active (structur- ally open) euchromatin or transcriptionally silent (condensed) Polycomb Repressor Complex 2 (PRC2) is an epigenetic effector heterochromatin. Heterochromatin can be further divided into a enzyme with key roles in gene silencing and establishment of constitutive form, which cannot convert to euchromatin, and a facultative heterochromatin. Mutations of this histone lysine facultative form, which retains that potential (1). The histone methyltransferase and its substrate H3K27 are linked to mul- proteins involved in packaging the DNA in each of these states tiple human pathologies, and PRC2 has been identified as a are decorated with complex, characteristic patterns of post- therapeutic target in cancer treatment. The H3K27 methylation translational modifications (PTMs) that contribute to the local activity of PRC2 is sensitive to the chromatin environment, in- structure of chromatin (2, 3). cluding the methylation state of H3K36 on the same histone Histone H3 contains several key lysine residues on its N- tail. The mechanistic basis of this negative cross-talk is poorly terminal tail, including H3K27 and H3K36, which are the sites of understood. The present work sheds light on this question by various regulatory PTMs. H3K27me3, catalyzed by PRC2, is identifying a regulatory feature on the catalytic subunit of known to be important to the establishment of gene silencing PRC2, EZH2, which acts as a specific sensor for H3K36 methyl- through the recruitment of the PRC1 silencing complex that is ation state. The work reveals an unusual mode of enzyme ultimately responsible for the establishment of facultative het- modulation by a substrate molecule. erochromatin (4–6), while H3K36me3 is commonly associated with active transcription within euchromatic regions (7). Notably, Author contributions: K.S.J., M.M.M., and T.W.M. designed research; K.S.J. performed both these PTMs are dynamic, and dedicated demethylase en- research; K.S.J., S.U.J., E.J.G., K.L.D., S.M.L., and P.W.L. contributed new reagents/analytic tools; K.S.J. and T.W.M. analyzed data; and K.S.J. and T.W.M. wrote the paper. zymes are responsible for their removal (8–10). The delicate balance between H3K27me3 and H3K36me2/3 is The authors declare no conflict of interest. critical to the establishment and maintenance of cellular identity This article is a PNAS Direct Submission. (11–13). Indeed, disruption of these methylation patterns is associ- Published under the PNAS license. ated with several pathologies. Mutations in the histone methyl- 1Present address: Department of Chemistry, King’s College London, SE1 1DB London, transferase (HMT) enzymes responsible for installing methylation at United Kingdom. both the H3K27 and H3K36 positions (i.e., PRC2 and NSD1-3/ 2To whom correspondence should be addressed. Email: [email protected]. SETD2, respectively) have been identified in numerous cancers This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. and overgrowth disorders (7, 14, 15). Both activating and inacti- 1073/pnas.1819029116/-/DCSupplemental. vating mutations of EZH2, the SET domain-containing catalytic Published online April 9, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1819029116 PNAS | April 23, 2019 | vol. 116 | no. 17 | 8295–8300 Downloaded by guest on October 2, 2021 binding partner can allosterically stimulate PRC2 activity in a Results manner analogous to H3K27me3 binding to EED (31) and has a PRC2 Activity Is Modulated by H3K36. We initiated our studies into role in targeting the core enzyme to relevant genomic loci along the basis of H3K27/H3K36 methylation cross-talk by performing with other factors, such as AEBP2 and PCLs (26, 33). HMT assays using purified recombinant PRC2 complexes and PRC2 activity is known to be sensitive to the modification various designer chromatin substrates containing methyl-lysine status of histones, particularly on the H3 tail (Fig. 1). Re- analogs (SI Appendix, Fig. S1). Consistent with previous reports markably, the same PTM chemotype (e.g., lysine methylation) (34, 35), PRC2 activity was found to be significantly higher on can have opposite effects on activity, depending on the sequence H3K36cme0 (i.e., unmodified) mononucleosome substrates position. Thus, while H3K27me3 leads to stimulation of PRC2, compared with those containing H3K36cme2/3, as measured by H3K36me3—which marks actively transcribed chromatin— scintillation counting using 3H-labeled SAM (Fig. 2A). Similar inhibits enzyme activity (34, 35). Notably, the two PTMs are results were obtained by Western blot analysis using antibodies rarely found to coexist on the same histone tail in nature (34–36). specific to methylated H3K27 (Fig. 2B). Substitution of H3K36 Indeed, it is thought that H3K36me3 functions to block hetero- with alanine or arginine also resulted in diminished H3K27 chromatin spreading by antagonizing PRC2 activity in cis (13, 34, methylation, while methionine and isoleucine substitutions had a 35). Consistent with this idea, reduction of H3K36 methylation more modest impact on PRC2 function (Fig. 2C). levels in cells leads to a genome-wide increase in H3K27 methyl- To better understand the origins of these effects, we turned to ation and an associated derepression of polycomb gene silencing more detailed kinetic analyses. In preliminary studies, we found (12, 13). Unlike with H3K27me3, for which the mechanism of that the use of 12mer nucleosome array substrates allowed for PRC2 stimulation is well understood and involves a long-range al- the measurement of enzymatic activity under conditions appro- losteric
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