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Histone H3Q5 Serotonylation Stabilizes H3K4 Methylation and Potentiates Its Readout

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Histone H3Q5 Serotonylation Stabilizes H3K4 Methylation and Potentiates Its Readout Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout Shuai Zhaoa,1, Kelly N. Chuhb,1, Baichao Zhanga,1, Barbara E. Dulb, Robert E. Thompsonb, Lorna A. Farrellyc,d, Xiaohui Liue, Ning Xue, Yi Xuee, Robert G. Roederf, Ian Mazec,d,2, Tom W. Muirb,2, and Haitao Lia,g,2 aMinistry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; bDepartment of Chemistry, Princeton University, Princeton, NJ 08540; cNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; dDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029; eNational Protein Science Technology Center, School of Life Sciences, Tsinghua University, Beijing 100084, China; fLaboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065; and gTsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China Edited by Peter Cheung, York University, Toronto, ON, Canada, and accepted by Editorial Board Member Karolin Luger November 12, 2020 (received for review August 7, 2020) Serotonylation of glutamine 5 on histone H3 (H3Q5ser) was recently established that H3K4me3 regulates gene expression through re- identified as a permissive posttranslational modification that coexists cruitment of nuclear factors that contain reader domains specific with adjacent lysine 4 trimethylation (H3K4me3). While the resulting for the mark. These include ATP-dependent chromatin remod- dual modification, H3K4me3Q5ser, is enriched at regions of active eling enzymes, as well as several transcription factors (13). The gene expression in serotonergic neurons, the molecular outcome latter include the general transcription factor complex, TFIID, underlying H3K4me3–H3Q5ser crosstalk remains largely unexplored. which engages the mark through its plant homeodomain (PHD) Herein, we examine the impact of H3Q5ser on the readers, writers, finger domain-containing TAF3 subunit, thereby stimulating and erasers of H3K4me3. All tested H3K4me3 readers retain binding preinitiation complex formation (14, 15). to the H3K4me3Q5ser dual modification. Of note, the PHD finger of Recently, we uncovered a PTM on the histone H3 tail whereby TAF3 favors H3K4me3Q5ser, and this binding preference is depen- the monoamine serotonin (5-hydroxytryptamine, 5-HT) is cova- dent on the Q5ser modification regardless of H3K4 methylation lently added to the side-chain of glutamine-5 by the writer enzyme, states. While the activity of the H3K4 methyltransferase, MLL1, Transglutaminase 2 (TGM2) (16) (Fig. 1A). Notably, the H3Q5ser BIOCHEMISTRY is unaffected by H3Q5ser, the corresponding H3K4me3/2 erasers, markwasfoundtocooccurwithneighboringH3K4me3onthe KDM5B/C and LSD1, are profoundly inhibited by the presence of B the mark. Collectively, this work suggests that adjacent H3Q5ser same histone tail (Fig. 1 ). This dual mark (i.e., H3K4me3Q5ser) is potentiates H3K4me3 function by either stabilizing H3K4me3 from enriched in euchromatin and correlates strongly with permissive dynamic turnover or enhancing its physical readout by down- gene expression during neuronal differentiation. Moreover, the stream effectors, thereby potentially providing a mechanism for dual mark was found to potentiate the interaction with TFIID fine-tuning critical gene expression programs. compared to H3Kme3 alone, offering a potential mechanistic link to active transcription. histone modification | H3Q5 serotonylation | H3K4me3 | modification crosstalk | designer chromatin Significance he eukaryotic genome is packaged in the form of chromatin Histone H3Q5ser and H3K4me3 can coexist as a dual modifi- T(1). The basic repeating unit of this nucleoprotein complex is cation pattern to regulate active gene transcription. However, the nucleosome, which is comprised of an octameric core of the molecular impact of H3Q5ser on H3K4me3 recognition and histone proteins, two copies each of H2A, H2B, H3, and H4, catalysis remains largely unexplored. Here, we profile the in- around which 146 base pair (bp) of double-stranded DNA is fluence of H3Q5ser on H3K4 methylation readers, writers, and wrapped. Histones are elaborated by numerous posttranslational erasers. Interestingly, all tested H3K4me3 readers bind H3K4me3Q5ser. modifications (PTMs, or marks), which are installed and re- Furthermore, while the activity of the H3K4 methyltransferase, moved by chromatin-modifying enzymes, commonly referred to MLL1, is unaffected by H3Q5ser, corresponding H3K4 methyl- as writers and erasers (2). Histone PTMs, alone or in combina- ation erasers are profoundly inhibited by the presence of the tion, can alter the local activity of chromatin, either by affecting mark. Collectively, this work suggests that H3Q5ser plays an the intrinsic structure and/or stability of the nucleoprotein augmenting role when coupled with the installation of H3K4 complex, or by acting as targeting vectors for nuclear factors that methylation so as to potentiate downstream outputs via chro- contain so-called reader domains that bind to marks in specific matin readers and erasers. The present work exemplifies the sequence contexts (3). Thus, by acting as dynamic signaling hubs, importance of modification crosstalk in gene regulation. histone marks play an essential role in epigenetic regulation, and, not surprisingly, dysregulation of these modifications by abnor- Author contributions: I.M., T.W.M., and H.L. conceived research; S.Z., K.N.C., and B.Z. – designed research; S.Z., K.N.C., and B.Z. performed research; B.E.D., R.E.T., L.A.F., X.L., mal inputs or outputs is frequently associated with disease (4 6). N.X., Y.X., and R.G.R. contributed new reagents/analytic tools; S.Z., K.N.C., B.Z., T.W.M., One of the most studied epigenetic marks is trimethylation of and H.L. analyzed data; and S.Z., K.N.C., B.Z., I.M., T.W.M., and H.L. wrote the paper. lysine 4 on histone H3 (H3K4me3). This evolutionarily conserved The authors declare no competing interest. PTM is associated with active transcription and is highly enriched at This article is a PNAS Direct Submission. P.C. is a guest editor invited by the promoter regions and transcription start sites (7–9). The H3K4me3 Editorial Board. mark is installed by a group of dedicated writer enzymes that in- Published under the PNAS license. clude the mixed-lineage leukemia (MLL) family of S-adenosyl 1S.Z., K.N.C., and B.Z. contributed equally to this work. methionine (SAM)-dependent protein lysine methyltransferases 2To whom correspondence may be addressed. Email: [email protected], muir@ (10). H3K4me2/3 is known to be dynamic, and its removal is princeton.edu, or [email protected]. catalyzed by lysine histone demethylases, of which there are This article contains supporting information online at https://www.pnas.org/lookup/suppl/ several subfamilies (11), including the Jumonji C (JmjC) domain- doi:10.1073/pnas.2016742118/-/DCSupplemental. containing proteins KDM5A/B/C/D and LSD1/2 (12). It is well Published February 1, 2021. PNAS 2021 Vol. 118 No. 6 e2016742118 https://doi.org/10.1073/pnas.2016742118 | 1of7 Downloaded by guest on September 23, 2021 Fig. 1. Profiling of H3K4me3 readers in response to H3K4me3Q5ser dual modification. (A) Structure of the Q5ser modification. Carbon atoms are shown in yellow; nitrogen atoms are shown in blue; oxygen atoms are shown in red. (B) The coexistence mode of the H3K4me3Q5ser dual modification. (C) SPRi signal of H3(1–15)K4me3 and H3(1–15)K4me3Q5ser peptides toward H3K4me3 readers. The values of SPRi signals are the blanked average signal during 250–300 s of the association curve in SI Appendix, Fig. S1A.(D) Titration curves and fitting curves of H3(1–15)K4me3 and H3(1–15)K4me3Q5ser peptides titrated into H3K4me3 readers. KD values are provided (see SI Appendix, Table. S1 for fitting parameters and error). (E) Summary of binding affinities determined in D.(F) ITC curves of TAF3PHD binding to histone H3 unmodified vs. Q5ser, K4me1 vs. K4me1Q5ser, K4me2 vs. K4me2Q5ser, and K4me3 vs. K4me3Q5ser peptides. KD values are provided (see SI Appendix, Table S1 for fitting parameters and error). (G) ITC curves of TAF3PHD binding to histone H3K4me3Q5(ser-analog) peptides. KD values are provided (see SI Appendix, Table S1 for fitting parameters and error). While the discovery of H3Q5ser represented an example of spatial and temporal changes in gene expression are achieved monoaminylation of a histone target, the intricacies of H3K4me3– (17). In this study, we profiled H3K4me3 readers in the context Q5ser biochemical crosstalk (i.e., how each mark influences the of adjacent H3Q5ser. All tested H3K4me3 readers tolerate the others installation and/or removal) and its epigenetic consequences H3K4me3Q5ser dual modification. Of note, the PHD finger of remain largely unexplored. Elucidating the role of local epigenetic TAF3 favors H3K4me3Q5ser, and this binding preference relies environments in regulating the communication between histone on the Q5ser modification regardless of H3K4 methylation states. readers, writers, and erasers is critical to understanding how Additionally, and perhaps most strikingly, we provide evidence 2of7 | PNAS Zhao et al. https://doi.org/10.1073/pnas.2016742118 Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates
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