Abstract
The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
RNA-Seq data have been deposited to the Gene Expression Omnibus under accession GSE102250. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org/) via the PRIDE partner repository72 with dataset identifier PXD009317. The damaging variants reported as disease causing in this article were deposited in the ClinVar database under study accession SUB2871008.
References
Ronan, J. L., Wu, W. & Crabtree, G. R. From neural development to cognition: unexpected roles for chromatin. Nat. Rev. Genet. 14, 347–359 (2013).
Ropers, H.-H. & Hamel, B. C. J. X-linked mental retardation. Nat. Rev. Genet. 6, 46–57 (2005).
Lubs, H. A., Stevenson, R. E. & Schwartz, C. E. Fragile X and X-linked intellectual disability: four decades of discovery. Am. J. Hum. Genet. 90, 579–590 (2012).
Bjornsson, H. T. The Mendelian disorders of the epigenetic machinery. Genome Res. 25, 1473–1481 (2015).
Tapias, A. & Wang, Z.-Q. Lysine acetylation and deacetylation in brain development and neuropathies. Genomics Proteomics Bioinformatics 15, 19–36 (2017).
Lee, J.-H., Hart, S. R. L. & Skalnik, D. G. Histone deacetylase activity is required for embryonic stem cell differentiation. Genesis 38, 32–38 (2004).
Hsieh, J., Nakashima, K., Kuwabara, T., Mejia, E. & Gage, F. H. Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc. Natl Acad. Sci. USA 101, 16659–16664 (2004).
Mews, P. et al. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 546, 381–386 (2017).
Tessarz, P. & Kouzarides, T. Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell Biol. 15, 703–708 (2014).
Shogren-Knaak, M. et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006).
Keller, C. I. & Akhtar, A. The MSL complex: juggling RNA–protein interactions for dosage compensation and beyond. Curr. Opin. Genet. Dev. 31, 1–11 (2015).
Philippakis, A. A. et al. The Matchmaker Exchange: a platform for rare disease gene discovery. Hum. Mutat. 36, 915–921 (2015).
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
Smith, E. R. et al. A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16. Mol. Cell. Biol. 25, 9175–9188 (2005).
Taipale, M. et al. hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells. Mol. Cell. Biol. 25, 6798–6810 (2005).
GTEx Consortium. Human genomics. The Genotype–Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
Kadlec, J. et al. Structural basis for MOF and MSL3 recruitment into the dosage compensation complex by MSL1. Nat. Struct. Mol. Biol. 18, 142–149 (2011).
Zhao, X. et al. Crosstalk between NSL histone acetyltransferase and MLL/SET complexes: NSL complex functions in promoting histone H3K4 di-methylation activity by MLL/SET complexes. PLoS Genet. 9, e1003940 (2013).
Gelbart, M. E., Larschan, E., Peng, S., Park, P. J. & Kuroda, M. I. Drosophila MSL complex globally acetylates H4K16 on the male X chromosome for dosage compensation. Nat. Struct. Mol. Biol. 16, 825–832 (2009).
Akhtar, A. & Becker, P. B. Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Mol. Cell 5, 367–375 (2000).
Chelmicki, T. et al. MOF-associated complexes ensure stem cell identity and Xist repression. eLife 3, e02024 (2014).
Tukiainen, T. et al. Landscape of X chromosome inactivation across human tissues. Nature 550, 244–248 (2017).
Cai, Y. et al. Subunit composition and substrate specificity of a MOF-containing histone acetyltransferase distinct from the male-specific lethal (MSL) complex. J. Biol. Chem. 285, 4268–4272 (2010).
Morales, V., Regnard, C., Izzo, A., Vetter, I. & Becker, P. B. The MRG domain mediates the functional integration of MSL3 into the dosage compensation complex. Mol. Cell. Biol. 25, 5947–5954 (2005).
Kim, D. et al. Corecognition of DNA and a methylated histone tail by the MSL3 chromodomain. Nat. Struct. Mol. Biol. 17, 1027–1029 (2010).
Vaquero, A. et al. SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev. 20, 1256–1261 (2006).
Bonenfant, D. et al. Analysis of dynamic changes in post-translational modifications of human histones during cell cycle by mass spectrometry. Mol. Cell. Proteomics 6, 1917–1932 (2007).
McManus, K. J. & Hendzel, M. J. The relationship between histone H3 phosphorylation and acetylation throughout the mammalian cell cycle. Biochem. Cell Biol. 84, 640–657 (2006).
Conrad, T. & Akhtar, A. Dosage compensation in Drosophila melanogaster: epigenetic fine-tuning of chromosome-wide transcription. Nat. Rev. Genet. 13, 123–134 (2012).
Conrad, T. et al. The MOF chromobarrel domain controls genome-wide H4K16 acetylation and spreading of the MSL complex. Dev. Cell 22, 610–624 (2012).
Kasowski, M. et al. Extensive variation in chromatin states across humans. Science 342, 750–752 (2013).
De Ruijter, A. J. M., Van Gennip, A. H., Caron, H. N., Stephan, K. & Van Kuilenburg, A. B. P. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J. 370, 737–749 (2003).
Marks, P. A. & Breslow, R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat. Biotechnol. 25, 84–90 (2007).
Bradner, J. E. et al. Chemical phylogenetics of histone deacetylases. Nat. Chem. Biol. 6, 238–243 (2010).
Coni, S. et al. Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH medulloblastoma. Sci. Rep. 7, 44079 (2017).
Lillico, R., Sobral, M. G., Stesco, N. & Lakowski, T. M. HDAC inhibitors induce global changes in histone lysine and arginine methylation and alter expression of lysine demethylases. J. Proteomics 133, 125–133 (2016).
Schölz, C. et al. Acetylation site specificities of lysine deacetylase inhibitors in human cells. Nat. Biotechnol. 33, 415–423 (2015).
Tzogani, K. et al. EMA review of panobinostat (Farydak) for the treatment of adult patients with relapsed and/or refractory multiple myeloma. Oncologist 23, 631–636 (2018).
Volmar, C.-H. & Wahlestedt, C. Histone deacetylases (HDACs) and brain function. Neuroepigenetics 1, 20–27 (2015).
Dulac, C. Brain function and chromatin plasticity. Nature 465, 728–735 (2010).
Thomas, T., Dixon, M. P., Kueh, A. J. & Voss, A. K. Mof (MYST1 or KAT8) is essential for progression of embryonic development past the blastocyst stage and required for normal chromatin architecture. Mol. Cell. Biol. 28, 5093–5105 (2008).
Gupta, A. et al. The mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis. Mol. Cell. Biol. 28, 397–409 (2008).
Sheikh, B. N. et al. MOF maintains transcriptional programs regulating cellular stress response. Oncogene 35, 2698–2710 (2016).
Chatterjee, A. et al. MOF acetyl transferase regulates transcription and respiration in mitochondria. Cell 167, 722–738 (2016).
Koolen, D. A. et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat. Genet. 38, 999–1001 (2006).
Sharp, A. J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat. Genet. 38, 1038–1042 (2006).
Shaw-Smith, C. et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat. Genet. 38, 1032–1037 (2006).
Füllgrabe, J. et al. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature 500, 468–471 (2013).
Morgan, T. H. Sex-limited inheritance in Drosophila. Science 32, 120–122 (1910).
Dobyns, W. B. et al. Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am. J. Med. Genet. A 129A, 136–143 (2004).
Zerem, A. et al. The molecular and phenotypic spectrum of IQSEC2-related epilepsy. Epilepsia 57, 1858–1869 (2016).
Lezin, A. et al. Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients. Blood 110, 3722–3728 (2007).
Lelieveld, S. H. et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat. Neurosci. 19, 1194–1196 (2016).
Samocha, K. E. et al. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46, 944–950 (2014).
Gilissen, C. et al. Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344–347 (2014).
Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 542, 433–438 (2017).
Retterer, K. et al. Clinical application of whole-exome sequencing across clinical indications. Genet. Med. 18, 696–704 (2016).
Thevenon, J. et al. Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test. Clin. Genet. 89, 700–707 (2016).
Pajusalu, S., Reimand, T. & Õunap, K. Novel homozygous mutation in KPTN gene causing a familial intellectual disability-macrocephaly syndrome. Am. J. Med. Genet. A 167, 1913–1915 (2015).
Dobin, A. et al. STAR: ultrafast universal RNA-Seq aligner. Bioinformatics 29, 15–21 (2013).
Thåström, A. et al. Sequence motifs and free energies of selected natural and non-natural nucleosome positioning DNA sequences. J. Mol. Biol. 288, 213–229 (1999).
Dyer, P. N. et al. Reconstitution of nucleosome core particles from recombinant histones and DNA. Methods Enzymol. 375, 23–44 (2004).
Basilicata, M. F., Frank, M., Solter, D., Brabletz, T. & Stemmler, M. P. Inappropriate cadherin switching in the mouse epiblast compromises proper signaling between the epiblast and the extraembryonic ectoderm during gastrulation. Sci. Rep. 6, 26562 (2016).
Shevchenko, A., Tomas, H., Havlis, J., Olsen, J. V. & Mann, M. In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat. Protoc. 1, 2856–2860 (2006).
Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2, 1896–1906 (2007).
Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016).
Kuhn, M. et al. caret: classification and regression training. R Package Version 6.0--47 (2015).
Stemmler, M. P., Hecht, A. & Kemler, R. E-cadherin intron 2 contains cis-regulatory elements essential for gene expression. Development 132, 965–976 (2005).
Kim, D., Langmead, B. & Salzberg, S. L. HISAT: a fast spliced aligner with low memory requirements. Nat. Methods 12, 357–360 (2015).
Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014).
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-Seq data with DESeq2. Genome Biol. 15, 550 (2014).
Vaudel, M. et al. Exploring the potential of public proteomics data. Proteomics 16, 214–225 (2016).
Acknowledgements
We are grateful to the patients and their families for their cooperation and interest in the study. We thank N. Iovino, B. Sheikh, and I. Ilik for critical reading of the manuscript. We also thank C. Pessoa Rodrigues and A. Karoutas for technical help, insightful discussion, and advice. We thank V. Bhardwaj for advice and consulting on RNA-Seq analysis, and S. Kübart, A. Schröer, J. Wirth, and H.-G. Nothwang for help with inversion breakpoint mapping. We thank L. Wells for patient recruitment and clinical data collection. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust, Department of Health, and Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or Department of Health. This study has UK Research Ethics Committee (REC) approval (10/H0305/83, granted by the Cambridge South REC; and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research through the Comprehensive Clinical Research Network. This study makes use of DECIPHER (see URLs), which is funded by Wellcome. Sequencing for patient 12 was provided by the Center for Mendelian Genomics at the Broad Institute of MIT and Harvard, and was funded by the National Human Genome Research Institute, National Eye Institute, and National Heart, Lung and Blood Institute grant UM1 HG008900 to D. MacArthur and H. Rehm. This work was supported by CRC992, CRC1140, and CRC746 (awarded to A.A.). It was also supported by the council of Burgundy, German Human Genome Program (grant number 01KW99087) and National Genome Research Network (project numbers 01GR0105 and 01GS08160), awarded to V.M.K. and A.R., respectively. C.I.K.V. was supported by a Human Frontier Science Program long-term fellowship (000233/2014-L).
Author information
Authors and Affiliations
Consortia
Contributions
M.F.B., A.A., and J.T. conceived the project and planned the experiments. The review of phenotypes and sample collection were performed by J.M., I.B., M.K., H.G.B., O.V., K.Õ., B.M., T.Y.T., S.V., K.L., A.R., D.S.J., A.F., V.M., R.B.F., V.M.K., A.-L.B., L.F., S.E.C., J.T., C.T.R., I.v.d.B., M.T.C., and M.W. Fibroblast isolation, tissue section preparation and processing, cell culture, protein analysis, FACS, immunostaining, microscopy, drug treatment experiments, ChIP, RNA expression analysis, and IPA pathway analyses were performed by M.F.B. A.-L.B. initiated data sharing and compiled patients’ clinical data. G.S. performed deep-sequencing data analysis and manuscript editing. C.I.K.V. contributed to the design, analysis, and interpretation of the experiments and data. T.A. performed cloning of the MSL3 expression constructs and co-immunoprecipitations. W.G.S. and G.M. performed LC-MS sample preparation and analysis. T.R. purified recombinant proteins, and performed HAT assays and in silico modeling. Ethical consultation was provided by L.F. Data analysis for exome and frequency calculation was performed by Y.D., S.P., J.T., A.-L.B., C.G., and R.P. The manuscript was written and edited by C.I.K.V., M.F.B., A.A., and J.T. All authors reviewed, edited, and approved the paper.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Integrated supplementary information
Supplementary Figure 1 MSL3 variants cause a novel syndrome.
a, Representation of the MSL3 patient countries of origin. b, Sanger sequencing confirming the skipping of MSL3 exon 11 in P1 cDNA. The allelic ratio was in favor of random X inactivation. Right, cropped agarose gel picture of RT–PCR products. c, Schematic representation of X chromosome inversion of P16. d, Patient pedigrees. No MSL3 variant could be detected in the parents of patients P1–P11 (the father of patient P10 could not be tested). P16’s mother is reported as mildly affected with no clinical details provided. Her X chromosome inversion occurred de novo. e, Heat map representing RNA-Seq data for MSL3 in the developing human brain compared to other members of the MSL complex. Data were retrieved from https://www.ebi.ac.uk/gxa/home/. f, Amino acid sequence alignment of MSL3 orthologs showing that the mutated residues are highly conserved throughout evolution.
Supplementary Figure 2 Characterization of MSL3 patient-derived fibroblasts.
a, FFPE skin sections from Control (ctrl) and P1/P2/P14 stained with H&E. The dashed line distinguishes dermis and epidermis layers. Architectural skin layers are demarcated. Scale bar, 20 μm. Patients donated n = 1 skin sample; at least two sections per slide were analyzed. SB, stratum basale; SL, stratum lucidum; SS, stratum spinosum; SC, stratum corneum. b, Immunostaining for H3K27me3 (red) in primary HDFs. Scale bar, 5 µm. The staining was repeated twice with similar results. c, Cropped immunoblots for H4K16ac and total histone H3 as well as H3 and H4 pan-acetylation in additional HDF lines. The experiment was repeated twice with similar results. d, Sashimi plot derived from MiSeq results showing exon skipping in P1 but not P2 or Control (ctrl) HDF cDNA. e, Distribution of identified protein intensities measured in LC-MS/MS experiments before (left) and after (right) normalization. Protein intensities as well as modified site intensities were normalized and scaled by adjusting the centers of the distributions around zero to account for loading differences in SDS-PAGE. Box plots are centered on the median with the lower and upper hinges corresponding to the first and third quartiles. Normalized values were used for further statistical analysis as described in Supplementary Table 2. f, Heat map representing all acetyl (K), mono- and trimethyl (R-K) histone modification normalized intensities detected over the bulk histone background level as in Supplementary Table 2. g, Proliferation curve in P1, P2 and P14 compared to Control (ctrl). The center value at each time point represents the mean of n = 2 independent experiments. h, FACS cell cycle analysis of Control (ctrl) andP1/P2/P14 HDFs, Propidium iodide was used to define cell cycle phases. Bar plots represent the mean of n = 2 independent experiments with overlaid data points. i, RT–qPCR analysis of senescence markers P16-INK4A and P21-WAF displayed as dot plots. Expression levels were normalized to RPLP0 and expressed relative to Control (ctrl). Each data point represents an independent experiment (n) with the center line representing the mean ± s.e.m. when applicable. P values were determined by ordinary one-way ANOVA followed by Bonferroni multiple-test correction. Further details and statistical test values are provided in Supplementary Table 5. j, Representative DIC images of β-galactosidase activity assays performed in Control (ctrl) and P1/P2/P14 HDFs. The experiment was repeated three times with similar results. k, Representative FACS analysis of MKI67 (x axis) and H4K16ac (y axis) in Control (ctrl) and P1/P2/P14 HDFs. Quadrants show the percentage of cells with relative abundance of cell populations. The experiment was repeated twice with similar results.
Supplementary Figure 3 Validation of transcriptional responses in MSL3 patients.
a, MA plot comparing the mean of the normalized counts versus the log2[fold-change] obtained from RNA-Seq of patients versus Control (ctrl) HDFs (n = 2 passages of Control were compared with n = 2 passages of P1, P2 and P14 each). DE genes (FDR cutoff of 0.05) are marked in red. b, H4K16ac ChIP–qPCR analysis of H3F3B and respective expression levels from RNA-Seq (normalized read counts) displayed as dot plots. H4K16ac ChIP–qPCR enrichment values were calculated relative to input and expressed as a fold change enrichment over the negative control, KLK3. Each data point represents an independent experiment (n) with the center line representing the mean ± s.e.m. where applicable. c, RT–qPCR expression analysis in HDFs displayed as dot plots. Expression levels were normalized to RPLP0 and expressed relative to Control (ctrl). Each data point represents an independent experiment (n) with the center line representing the mean ± s.e.m. where applicable. P values were determined by ordinary one-way ANOVA followed by Bonferroni multiple-test correction. Further details and statistical test values are provided in Supplementary Table 5. d, Immunohistochemistry for the serotonin receptor HTR7 and netrin receptor UNC5B on Control (ctrl) and patient-derived FFPE skin sections. Similar staining results were obtained in n = 2 sections per slide. e, RT–qPCR expression analysis in male and female HDFs upon MSL3 knockdown (KD) displayed as bar plots representing the mean ± s.e.m. Expression levels were normalized to RPLP0 and expressed relative to scrambled siRNA (scramble). The same data points for ZNF185 and SPON2 are also shown in Fig. 3 and are illustrated again for comparative purposes. Each overlaid data point represents the number (n) of independent experiments.
Supplementary Figure 4 Response to HDACi in MSL3 patient cells.
a, Heat map representing histone modification changes upon HDACi treatments (dataset from Nat. Biotechnol. 10.1038/nbt.3130, 2015). b, Cropped immunoblot for H4K16ac, pan-acetylated H3 and H4, H3K27me3, H3K4me1 and H3 for nuclear extracts of Control HDFs treated with HDACi. The same extracts were separated on a Coomassie-stained gel serving as loading control. The experiment was repeated twice with similar results. c, RT–qPCR of acetylation-sensitive targets in control HDFs. The bar plot represents the mean of n = 2 independent experiments with overlaid individual data points. d, Cropped immunoblot of P1/P2/P14 HDF nuclear extracts upon LBH-589 treatment. The experiment was repeated twice with similar results. e, RT–qPCR of P1/P2/P14 HDFs treated with four different HDACi: SAHA (vorinostat, HDAC class I and II inhibitor), LBH-589 (panobinostat, pan-HDACi) and MGCD0103 (mocetinostat, HDACi class I and IV). Expression levels are normalized to RPLP0, calculated relative to Control (ctrl without treatment) and shown as dot plots. Each data point represents (n) independent experiments with the center line representing the mean ± s.e.m. where applicable. f, Scheme representing the number of DE genes upon LBH-589 treatment. g, Heat map representing z-scores on the MSL3 patients DE downregulated (left; n = 196) and DE upregulated (right; n = 323) genes upon LBH-589 treatment obtained by RNA-Seq (P1/P2/P14, 2 passages). h, Dot plots of normalized RNA-Seq read counts for DNA damage and cell cycle marker genes before and after treatment with LBH-589. The center line represents the mean of n = 2 independent experiments. i, Representative DIC images upon LBH-589 treatment of Control (ctrl) and P1/P2/P14 HDFs at 0, 24 and 48 h after creating a gap area.
Supplementary Figure 5 Uncropped western blots, agarose and Coomassie gel pictures, and gating strategy example.
To illustrate molecular weight markers, epi-white and chemiluminescence pictures were merged in the display (respective blots are marked with an asterisk). Actual figure panels represent only chemiluminescence and not the merged pictures. Cropped regions are framed. Representative gating strategy for excluding debris (top) and doublets (bottom) in flow cytometry analysis of 1 × 104 events. Singlets are defined on the forward scatter (height) versus forward scatter (area) dot plot.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–5 and Supplementary Note
Supplementary Table 1
Clinical description of the 16 patients reported in this study
Supplementary Table 2
Normalized LC-MS limma analysis results in patients versus controls (n = 3 controls, n = 6 patients)
Supplementary Table 3
DE gene lists of control versus MSL3 patient HDFs, KEGG (IPA) pathway analysis for disease and Molecular Function of DE genes, LBH-589 treatment effect on DE genes, and OMIM tables for down, up and rescued transcripts
Supplementary Table 4
DE gene lists upon LBH-589 treatment and KEGG (IPA) pathways scores for Disease and Function
Supplementary Table 5
Primer list and details of statistical analyses
Rights and permissions
About this article
Cite this article
Basilicata, M.F., Bruel, AL., Semplicio, G. et al. De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nat Genet 50, 1442–1451 (2018). https://doi.org/10.1038/s41588-018-0220-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41588-018-0220-y
This article is cited by
-
Novel protein-truncating variants of a chromatin-modifying gene MSL2 in syndromic neurodevelopmental disorders
European Journal of Human Genetics (2024)
-
H4K16ac activates the transcription of transposable elements and contributes to their cis-regulatory function
Nature Structural & Molecular Biology (2023)
-
Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice
Nature Communications (2021)
-
A de novo variant in the human HIST1H4J gene causes a syndrome analogous to the HIST1H4C-associated neurodevelopmental disorder
European Journal of Human Genetics (2020)
-
Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation
Nature Communications (2020)