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Supplemental Information Supplemental Information Chromatin-to-nucleoprotamine transition is controlled by the histone H2B variant TH2B Emilie Montellier1, Fayçal Boussouar1, Sophie Rousseaux1, Kai Zhang2, Thierry Buchou1, François Fenaille3, Hitoshi Shiota1, Alexandra Debernardi1, Patrick Héry4, Sandrine Curtet1, Mahya Jamshidikia1, Sophie Barral1, Hélène Holota5, Aurélie Bergon5, Fabrice Lopez5, Philippe Guardiola6, Karin Pernet7, Jean Imbert5, Carlo Petosa8, Minjia Tan9,10, Yingming Zhao9,10, Matthieu Gérard4, Saadi Khochbin1* 1 - INSERM, U823; Université Joseph Fourier - Grenoble 1; Institut Albert Bonniot, Grenoble, F-38700 France 2 - State Key Laboratory of Medicinal Chemical Biology & Department of Chemistry, Nankai University, Tianjin 300071, China 3 – Laboratoire d'Etude du Métabolisme des Médicaments, DSV / iBiTec-S / SPI, CEA Saclay, 91191 Gif sur Yvette, Cedex, France 4 - CEA, iBiTec-S, Gif-sur-Yvette, F-91191 France 5 - INSERM UMR_S 1090; TGML/TAGC, Aix-Marseille Université, Marseille, France 6 - INSERM, U892; Centre de Recherche sur le Cancer Nantes Angers et UMR_S 892; Université d’Angers; Plateforme SNP, Transcriptome & Epigénomique; Centre Hospitalier Universitaire d’Angers; Angers, F-49000 France 7 - INSERM U836; Université Joseph Fourier, Grenoble Institute of Neuroscience, Grenoble, F-38700 France, 8 - Institut de Biologie Structurale Jean-Pierre Ebel, UMR 5075 CEA-CNRS-Université Joseph Fourier, 41 Jules Horowitz, 38027 Grenoble cedex 1. 9 - Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA 10 - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P.R. China *Correspondance : Saadi Khochbin ([email protected]). 1 SUPPLEMENTAL DATA SUPPLEMENTAL FIGURE LEGENDS Figure S1. Generation of the Th2b tag knock-in and knock-down mouse models. A. Schematic representation of Th2b and Th2a genes. A “His-Flag-Ha” tag and a LoxP flanked Neo cassette were introduced by homologous recombination in fusion in frame with Th2b coding sequence replacing the STOP codon of the gene. The presence of the Neo cassette interferes with Th2b gene expression leading to the absence of TH2B expression in the spermatogenic cells of Th2bNeo/Neo mice. Crossing the Th2bNeo/Neo mice with transgenic CMV-Cre mice leads to the deletion of the Neo cassette and the expression of TH2B-tag. B. The shared regulatory region of Th2b and Th2a genes is shown in comparison with the corresponding rat sequence (in blue), where transcriptional regulatory elements have been characterized (indicated) (Huh et al., 1991). C. DNA prepared from Neo-resistant ES clones was subjected to southern blot analysis (left panel) using a 3’ external probe (indicated in A). Lane 1: heterozygous; lane 2 and 3: wild type. Heterozygous Th2b +/Neo mice were crossed to CMV-Cre mice to delete the Neo cassette. PCR (right panel) analysis distinguishes the wild type allele from the recombined allele (Th2bdelta-neo). Lanes 1 and 2: Th2bdelta-neo mice; lane 3: Th2b+/+ mouse. Figure S2 (related to Figure 4A and B). Mass spectrometry analysis of histones within TH2B-containing nucleosomes. Protein ID, Mascot scores and identified sequences coverage were obtained from Mascot search of high-resolution MS/MS spectra against the IPI mouse v3.74 protein sequence database. Searching parameters were set as described in the Experimental Procedures. All the identified tryptic peptides with Mascot scores above 20.0 are shown in red color. Figure S3. A. H2A.Z but not TH2B at gene TSS is associated with higher gene transcriptional activity. The overall expression of H2A.Z+ and H2A.Z-less gene categories (shown in Figure 4D) in both spermatocytes (spc) and round spermatids (R-Spt) are shown as box-plots. The expression values obtained from our transcriptomic experiments were normalized using the mean expression value of all genes in spermatocytes. * p value (t-test). B. FRAP experiment comparing the mobility of tagged and untagged GFP-TH2B. H1299 lung carcinoma cells stably expressing GFP-TH2B and GFP-TH2B-tag were established (GFP fluorescence in the corresponding cell lines is shown, upper panels). 2 The middle panel shows the time course of background-corrected fluorescence in bleached area, showing mean intensity and standard deviation from ten independent experiments for each protein (middle panel). The lower panel shows the FRAP profile analysis. FRAP profiles were compatible with the presence of two populations of mobile species, exhibiting high and low mobility. Individual -k t -k t FRAP curves were fit to the equation F(t) = A(1 – e 1 ) + B(1 – e 2 ), where F(t) is the background-corrected fluorescence at time t, A and B are the fraction of high- and low-mobility species, respectively, and k1 and k2 are the corresponding first-order rate constants. The half- lives (t1/2) of the high- and low-mobility species are given by ln2/k1 and ln2/k2, respectively, while the fraction of molecules that are immobile (on the time scale of the experiment) is given by 1-A-B. The table shows the summary of mobility parameters derived from FRAP analysis. The values represent the mean and standard deviation from ten independent experiments. Figure S4 (related to Figure 5). TH2B resists replacement by transition proteins and protamines in TH2B-tag expressing elongating spermatids. Co-detections of TH2B either with Transition Protein 2 (TP2, left panels) or with Protamine 1 (Prm1, right panels) (in the indicated colors) were performed on spermatogenic cell preparations from wild-type or Th2b+/tag testes by immunofluorescence using the corresponding antibodies. The squares indicate portions showed at higher magnification in Figure 5B. Figure S5. A (related to Figure 6B). Characterization of H2B isoforms accumulation in response to the absence of TH2B. Deconvoluted electrospray mass spectra of oxidized mouse histones H4 and H2B are shown. Histone identification was realized by matching experimentally determined masses with theoretical ones obtained from known amino acid sequences and post-translational modifications (Table S3). Heights of peaks corresponding to the different H2B variants were expressed relative to the heights of the major H4 peaks (unacetylated H4 + monoacetylated H4), and H2B/H4 ratios calculated for wild-type and TH2B-less mice. Numbers in parenthesis represent the variations of these H2B/H4 ratios between wild-type and TH2B-less mice, and are the mean values obtained from three independent biological replicates (see Figure S5B for more details). B (related to Figure 6B). H2B isoform levels in the presence (wild type) or absence (TH2B-less) of TH2B in spermatogenic cells. Heights of peaks on Figure S5A corresponding to the different H2B isoforms were expressed relative to those of the major H4 forms (unacetylated H4 + 3 monoacetylated H4). H2A/H4 ratio was also calculated for TH2B wild-type and TH2B-less mice as a control. Each bar is the average from three distinct histone extracts (from three distinct mice). Bars indicate standard deviations. The numbers on top of the red bars represent the fold changes of the H2B/H4 ratios between wild-type and TH2B-less mice. C. Equal sensitivity of dissociating nucleosomes from wild-type and TH2B-less elongating/condensing spermatids to MNase digestion. Nuclei from wild-type elongated/condensing spermatids or from the corresponding cells isolated from TH2B-less cells were extensively digested by MNase as described in the legend of Figure 5A. The agarose gel shows nucleosomal and sub- nucleosomal DNA fragments released by MNase digestion from the two cell types during the indicated times. D. (related to Figure 6C). MS/MS spectra of the modified peptides in histones in wild-type or TH2B-less spermatogenic cells. All the identified peptides with Mascot score above 20 were manually verified according to the rules described previously (Chen et al., 2005). All the identified MS/MS fragment ions (“b” and “y” ions) are shown in red color. All the identified PTM and propionylated sites were annotated. “Pr’’ indicates a propionylated N-terminal residue or lysine residue; “Kac”, “Kme”, “Kme2” and “Kcr” respectively indicate acetylation, mono-methylation, di-methylation and crotonylation at a lysine residue; “Rme” indicates mono- methylation at an arginine residue. Figure S6. TH2B-less males and females as well as Th2b+/tag female mice are fertile. A. No significant differences in the litter sizes could be observed when TH2B-less male and female mice were crossed compared to wild-type animals (n = 5 couples of each genotype). B. TH2B- tag expression in oocytes and eggs of Th2b+/tag female mice has no effect on the litter size when these mice are crossed with wild-type males compared to the litter size obtained for the corresponding wild-type animals (n = 6 couples of each genotype). Figure S7 (related to Figure 7A). TH2B disappears from embryonic chromatin during early development. Th2b+/tag embryo cryosections obtained at 13.5 days after birth were stained with the indicated antibodies. 4 SUPPLEMENTARY TABLES Table S1. List of histone variants identified in TH2B-containing nucleosomes. Mascot score for identified protein * (for detailed information, see Figure S2); The number of matched peptides for every identified protein (all identified tryptic peptides with Mascot scores above 20.0)** ; N/A Not detected. Table S2. List of specific peptides identified in every H1-isoform. * The specific peptide sequence was identified in every H1-isoform. ** Mascot score for identified peptides (all identified
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