Abstract
Tyrosine sulfation is a common posttranslational modification in mammals. To date, it has been thought to be limited to secreted and transmembrane proteins, but little is known about tyrosine sulfation on nuclear proteins. Here we report that SULT1B1 is a histone sulfotransferase that can sulfate the tyrosine 99 residue of nascent histone H3 in cytosol. The sulfated histone H3 can be transported into the nucleus and majorly deposited in the promoter regions of genes in chromatin. While the H3Y99 residue is buried inside octameric nucleosome, dynamically regulated subnucleosomal structures provide chromatin-H3Y99sulf the opportunity of being recognized and bound by PRMT1, which deposits H4R3me2a in chromatin. Disruption of H3Y99sulf reduces PRMT1 binding to chromatin, H4R3me2a level and gene transcription. These findings reveal the mechanisms underlying H3Y99 sulfation and its cross-talk with H4R3me2a to regulate gene transcription. This study extends the spectrum of tyrosine sulfation on nuclear proteins and the repertoire of histone modifications regulating chromatin functions.
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Data availability
The data that support the findings of this study are included in the main article and Supplementary Information files. The CUT&Tag-seq and RNA-seq data have been deposited in the Genome Sequence Archive for Human (GSA-Human) with the accession number HRA003214. The structural data used for structural analyses are available online: SULT1B1 (PDB ID: 3CKL); H3-H4 tetramer (PDB ID: 4Z2M); Hexasome and Nucleosome (PDB ID: 5GSE); PRMT1 (PDB ID: 6NT2). Source data are provided with this paper. The raw data for the mass spectrometry data have been depositied in the PRIDE database under accession ID PXD043754.
Change history
25 August 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41589-023-01424-0
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Acknowledgements
We thank Guohong Li at the Institute of Biophysics, Chinese Academy of Sciences, for discussion and scientific advice about the H3Y99sulf-modified nucleosome and subnucleosomal structures; Zhi Tan at Baylor College of Medical for scientific advice about the possible locations of H3Y99sulf on subnucleosomal structures; Li. Li at The University of Texas Health Science Center at Houston for the mass spectrum technical advice; and Ziying Xie from Dr. Zhonghui Tang’s laboratory at Sun Yat-sen University for addressing CUT&Tag-seq technical issues. This work was supported by the National Natural Science Foundation of China (grant nos. 32270642, 31970577 and 91957110 to Yugang Wang).
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Yugang Wang and K.L. conceived and designed the study and wrote the manuscript. W.Y., D.G., Yu Wang, J.H., S.Y., Y.G. and X.Z. performed the biochemistry experiments to identify the sulfotransferase activity of SULT1B1. X.B. and S.F. performed HPLC–MS/MS analysis to identify H3Y99sulf in cells. R.Z. and K.L. performed bioinformatics analyses. Z-C.L. performed in vitro assembly of tetramer, hexamer and octamer. M.L. and L.H. provided scientific insights. F.P., Y.L., N.L. and Y.R.G. performed structural analysis of SULT1B1 interacting with histone H3 and nucleosome variants.
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Extended data
Extended Data Fig. 1 Tyrosine sulfation is a novel type of histone modification.
(a), Identification of H3Y99phos peptide in HepG2 cells. MS/MS spectra of a phosphorylated histone H3 peptide (H3Y99phos) was derived from HepG2 cells (in vivo). The b ion refers to the N-terminal parts of the peptide, and the y ion refers to the C-terminal parts of the peptide. Data represent two independent experiments. (b) and (c), validation of H3Y99phos peptide in HepG2 cells. (b), The chromatographic elution profile from HPLC–MS/MS analysis of H3K99phos peptides derived from cultured HepG2 cells (in vivo) and the synthetic counterparts; (c), MS/MS spectra of a phosphorylated histone peptide (H3Y99phos) derived from HepG2 cells and its synthetic counterpart. The b ion refers to the N-terminal parts of the peptide, and the y ion refers to the C-terminal parts of the peptide. Data represent two independent experiments. (d) to (g), Generation of specific antibody against human H3Y99sulf. (d) and (e), H3Y99sulf-antibody specifically recognizes H3Y99sulf peptide. The binding of H3Y99sulf-antibody to H3Y99 control peptide (CEASEAYLVGLF), H3Y99phos-peptide (CEASEA-Y (phos)-LVGLFR), and H3Y99sulf-peptide (CEASEA-Y (Sulf)-LVGLFR) were tested by performing dot-blotting assay. Only H3Y99sulf peptide can block the application of H3Y99sulf-antibody in the dot-blotting assay; (f) and (g), H3Y99sulf peptide blocks the application of H3Y99sulf-antibody in western blotting and immunoprecipitation assays. H3Y99sulf-antibody was incubated with or without control peptide (10 μg/ml), H3Y99phos-peptide (10 μg/ml) and H3Y99sulf-peptide (10 μg/ml) for 24 hours before the western blotting and immunoprecipitation assays. Data represent three independent experiments. (h), Testing non-specific binding of H3Y99sulf-antibody. A microarray that contains histone peptides was used to test whether the developed H3Y99sulf-antibody read histone regions without H3Y99sulf. The antibody concentration is identical as used in the immunoblotting assays. Data represent one independent experiment.
Extended Data Fig. 2 Histone H3 tyrosine 99 sulfation is catalyzed by SULT1B1.
(a) to (d), H3Y99sulf is not regulated by the TPSTs. TPST1 and TPST2 in HepG2 and LM3 cells were depleted by expressing shRNAs against corresponding mRNAs. The knock-down efficiency was tested by performing real-time PCR (a) and (c), n = 4 biologically independent samples, two-sided t-test were conducted to calculate the P-value, the data is presented as the means±s.d. The level of H3Y99sulf in the cell lines with or without depletion of TPST1 and TPST2 was determined by performing immunoblotting assays with the indicated antibodies (b) and (d). The immunoblotting results represent three independent experiments. (e), Scheme of phenol sulfotransferase activities. (f), Validation of knock-down efficiency of phenol sulfotransferase family members. Real-time PCR assays were performed to confirm the knock-down of SULT1A1, SULT1B1, SULT1C1, SULT1E1, SULT2B1, and SULT4A1 in the culture HepG2 and LM3 cells, n = 4 biologically independent samples, two-sided t-test were conducted to calculate the P-value, the data is presented as the means±s.d. (g) to (i), SULT1B1 catalyzes the sulfation of histone H3Y99 in vitro. Purified histone H3 was incubated with PAPS and purified wide-type SULT1B1, inactive SULT1B1-H109A mutant34, and SULT1A1, respectively. A H3Y99sulf peptide was identified in the SULT1B1-mediated assay by performing HPLC-MS/MS analysis (g). Immunoblotting analyses were performed with the indicated antibodies (f) and (i). Representative images of triplicate experiments are shown. (j), The structure of SULT1B1 and the simulated active SULT1B1. (k), Superimposition of the structures of SULT1B1 in close and open states. (l), SULT1B1 cannot sulfate the H3Y99 in the assembled nucleosomes in vitro. Purified SULT1B1 and PAPS were incubated with in vitro assembled nucleosome. Immunoblotting analyses were performed with the indicated antibodies. Representative images of triplicate experiments are shown.
Extended Data Fig. 3 SULT1B1 cannot sulfate the H3Y99 in the assembled histone H3 in nucleosome variants.
(a) to (c), SULT1B1 cannot sulfate the H3Y99 in the assembled histone H3 in nucleosome variants. The simulated structure of active SULT1B1 binding with octameric (from PDB ID: 5GSE) (a), hexametric (from PDB ID: 5GSE) (b) and tetrameric nucleosomes (PDB ID: 4Z2M) (c) were performed, respectively. The steric clashes between the simulated structure of active SULT1B1 (green) and the histone H3-containing complexes (red) were highlighted in yellow.
Extended Data Fig. 4 Histone H3Y99 sulfation occurs in cytosol and associates with histone chaperones.
(a), Identification of H3Y99sulf in cytosol. The level of H3Y99sulf in cytosolic and nuclear fractions were compared. Immunoblotting analyses were performed with the indicated antibodies. Representative images of triplicate experiments are shown. (b), Identification of H3Y99sulf-associated histone chaperones. The H3Y99sulf-associated histone chaperones were examined by immunoblotting assays with the indicated antibodies, following the H3Y99sulf-immunoprecipiation. Representative images of triplicate experiments are shown. (c), Scheme of the histone chaperones facilitating H3-H4 heterodimerization, nuclear translocation, and depositing in distinct regions of chromatin.
Extended Data Fig. 5 Histone H3Y99 sulfation localizes on the surface of subnucleosomal structures.
(a), The chromatograph of synthesized full-length H3Y99sulf-histone H3 protein. (b), The mass spectrum of synthesized full-length H3Y99sulf-histone H3 protein. (c), The influence of H3Y99sulf on the interface between histone H3 and histone H4. The histones in the structures of histone H3-H4 heterodimer and H3Y99sulf-histone H3-H4 heterodimer are shown in surface and partially transparent mode, where the histone H3 molecule is shown in green and the histone H4 molecule is shown in cyan. The H3Y99 and H4F61 residues are shown in sticks, where the main chain of the sulfated H3Y99 residue is shown in black, the sulfonate atom is shown in yellow, and the sulfonate-associated oxygen atoms are shown in red. (d), The chromatograph of in vitro assembled histone H3-H4 tetramer, hexamer, and octamer bearing H3Y99sulf. (e), The SDS-PAGE electrophoresis of H3Y99sulf-modified histone H3-H4 tetramer, hexamer, and octamer. (f) and (g), The binding of H3Y99sulf-antibody to H3Y99sulf-modified subnucleosomal structures can be blocked by H3Y99sulf-peptide. H3Y99sulf-antibody was incubated with or without control peptide (10 μg/ml) and H3Y99sulf-peptide (10 μg/ml) for 24 hours before the addition of H3Y99sulf-tetramer (f), and H3Y99sulf-hexamer (g). Data represent three independent experiments.
Extended Data Fig. 6 Histone H3Y99 sulfation on the surface of subnucleosomal structures recruits PRMT1 to deposit H4R3me2a.
(a), The scheme of H3Y99sulf-localized α helix in histone H3. The structure of histone H3 is shown in gray. The α helix (from H3Q86 to H3K115) is shown in cyan. The H3Y99 residue is highlighted with red dashes. (b), The schemes of synthesized peptides. The secondary structures of the synthesized peptides are shown in cyan. The phosphonate group in the H3Y99phos-peptide is shown in magenta. The sulfonate group in the H3Y99sulf-peptide is shown in yellow. (c), Identification of H3Y99sulf-binding proteins. Venn diagram shows the overlapping of binding proteins to H3Y99 control peptide (blue), H3Y99phos-peptide (red) and H3Y99sulf-peptide (green), respectively. (d), Identification of PRMT1. The peptides of PRMT1 that identified in the HPLC-MS/MS analysis following the biotin-H3Y99sulf pull-down assays. (e) and (f), PRMT1 binds to H3Y99sulf-modified subnucleosomal structures. Purified PRMT1 was incubated with control peptide (10 μg/ml) and H3Y99sulf-peptide (10 μg/ml) for 24 hours before the addition of H3Y99sulf-tetramer (e) and H3Y99sulf-hexamer (f). Data represent three independent experiments. (g), SULT1B1 depletion reduced histone-binding of PRMT1 in cells. Immunoblotting assays were performed with the indicated antibodies. Representative images of triplicate experiments are shown. (h), Depletion of SULT1B1 reduced the occupancy of PRMT1 on chromatin. (P < 0.01). (i), The H3Y99sulf-binding has no effect on the catalytic activity of PRMT1. The activity of PRMT1 was examined by testing the production of H4R3me2a. Immunoblotting analyses were performed with the indicated antibodies. Representative images of triplicate experiments are shown. (j), Depletion of SULT1B1 reduced H4R3me2a in cells. Immunoblotting assay following pull-down experiment was performed with the indicated antibody. Representative images of triplicate experiments are shown. (k), Depletion of SULT1B1 reduced genome-wide occupancy of H4R3me2a on chromatin. (P < 0.01). (l), PRMT1 depletion showed no effect on the level of SULT1B1 and H3Y99sulf. Immunoblotting assays were performed with the indicated antibody. Representative images of triplicate experiments are shown.
Extended Data Fig. 7 Molecular basis of PRMT1 reading H3Y99sulf.
(a) to (c), Structure analyses of wild-type PRMT1 and PRMT1-(218–225)-mutant. (a), Crystal structure of wild-type PRMT1 (PDB: 6NT2); (b), predicted structures of PRMT1-(218–225)-mutant using Rosetta Backrub; (c), superimposition analysis of wild-type PRMT1 and PRMT1-(218–225)-mutant. (d), SDS-PAGE electrophoresis showing the purified GST-PRTM1 wild-type and GST-PRMT1-(218–225)-mutant. The image was from one experiment. (e), PRMT1-(218–225)-mutant has lower binding affinity to H3Y99sulf-enriched chromatin region. (P < 0.01). (f), PRMT1-(218–225)-mutant has lower enzymatic activity of depositing H4R3me2a. SAM and purified histone H4 were incubated with purified wild-type PRMT1 and PRMT1-(218–225)-mutant, respectively. The activities were examined by testing the production of H4R3me2a. Immunoblotting analyses were performed with the indicated antibodies. Representative images of triplicate experiments are shown.
Extended Data Fig. 8 H3Y99sulf regulates gene transcription.
(a), Genomic distribution of PRMT1 in HepG2 cells. The genomic distribution of highly enriched CUT & TAG-seq peaks for PRMT1 in HepG2 cells were analyzed and presented (FE ≥ 5, P < 0.01), one-sided P-value was returned by MACS2 and calculated based on Poisson distribution. (b), Genomic distribution of H4R3me2a in HepG2 cells. The genomic distribution of highly enriched CUT & TAG-seq peaks for H4R3me2a in HepG2 cells were analyzed and presented (FE ≥ 5, P < 0.01), one-sided P-value was returned by MACS2 and calculated based on Poisson distribution. (c), Average occupancy profiles of H3Y99sulf, PRMT1, and H4R3me2a in HepG2 cells expressing shRNA against non-target (blue) and SULT1B1 (red) around the transcription start site (TSS). (d), Combined analysis of CUT&TAG-seq and RNA-seq analyses revealing H3Y99sulf-enriched pathways that were significantly suppressed by the expression of shRNA against SULT1B1. Significantly downregulated pathways were identified via GSEA analysis (P < 0.05) and were enriched with downregulated genes (individual genes with fold enrichment >4 and P < 0.01 in CUT&TAG-seq analysis and P < 0.01 in RNA-seq analysis). The selected genes (PDK1, PGK1 and PFKFB3) were those that were most significantly suppressed (red nodes, fold enrichment >4 and P < 0.01 in CUT&TAG-seq analysis and P < 0.01 in RNA-seq analysis) or important members in the suppressed pathways. The blue node size reflects the number of significantly suppressed genes in the pathway. Edges represent more than one gene are shared between the pathways. (e), The enrichment of H3Y99sulf, PRMT1, and H4R3me2a at the promoter regions of PGK1, PDK1, and PFKFB3 was reduced after SULTB1 knockdown. In each row, the Y-axis represents fold enrichment level and the black bar represents the peak detected by MACS2 (P < 0.01), one-sided P-value was returned by MACS2 and calculated based on Poisson distribution.
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Yu, W., Zhou, R., Li, N. et al. Histone tyrosine sulfation by SULT1B1 regulates H4R3me2a and gene transcription. Nat Chem Biol 19, 855–864 (2023). https://doi.org/10.1038/s41589-023-01267-9
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DOI: https://doi.org/10.1038/s41589-023-01267-9
