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Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis

Nature Genetics volume 45, pages 308–313 (2013)Cite this article

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Abstract

The extracellular signal–related kinases 1 and 2 (ERK1/2) are key proteins mediating mitogen-activated protein kinase signaling downstream of RAS: phosphorylation of ERK1/2 leads to nuclear uptake and modulation of multiple targets1. Here, we show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 (refs. 2,3,4,5,6,7), causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple-suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. Mice with functional Erf levels reduced to ∼30% of normal exhibit postnatal multiple-suture synostosis; by contrast, embryonic calvarial development appears mildly delayed. Using chromatin immunoprecipitation in mouse embryonic fibroblasts and high-throughput sequencing, we find that ERF binds preferentially to elements away from promoters that contain RUNX or AP-1 motifs. This work identifies ERF as a novel regulator of osteogenic stimulation by RAS-ERK signaling, potentially by competing with activating ETS factors in multifactor transcriptional complexes.

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Figure 1: Clinical features of subjects heterozygous for ERF mutations.
Figure 2: Exon and domain structure of ERF and mutations identified in craniosynostosis.
Figure 3: Analysis of Erf in mouse mutants and embryonic fibroblasts.
Figure 4: Overlapping transcriptional targets of Erf and RUNX2 identified by ChIP-seq.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

NCBI Reference Sequence

References

  1. Plotnikov, A., Zehorai, E., Procaccia, S. & Seger, R. The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim. Biophys. Acta 1813, 1619–1633 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Mavrothalassitis, G.J. & Papas, T.S. Positive and negative factors regulate the transcription of the ETS2 gene via an oncogene-responsive–like unit within the ETS2 promoter region. Cell Growth Differ. 2, 215–224 (1991).

    CAS  PubMed  Google Scholar 

  3. Sgouras, D.N. et al. ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation. EMBO J. 14, 4781–4793 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Le Gallic, L., Sgouras, D., Beal, G. & Mavrothalassitis, G. Transcriptional repressor ERF is a Ras/mitogen-activated protein kinase target that regulates cellular proliferation. Mol. Cell Biol. 19, 4121–4133 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Le Gallic, L., Virgilio, L., Cohen, P., Biteau, B. & Mavrothalassitis, G. ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression. Mol. Cell Biol. 24, 1206–1218 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Polychronopoulos, S. et al. The transcriptional ETS2 repressor factor associates with active and inactive Erks through distinct FXF motifs. J. Biol. Chem. 281, 25601–25611 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. von Kriegsheim, A. et al. Cell fate decisions are specified by the dynamic ERK interactome. Nat. Cell Biol. 11, 1458–1464 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Ng, S.B. et al. Exome sequencing identifies the cause of a mendelian disorder. Nat. Genet. 42, 30–35 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Kim, H.-J. Erk pathway and activator protein 1 play crucial roles in FGF2-stimulated premature cranial suture closure. Dev. Dyn. 227, 335–346 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Shukla, V., Coumoul, X., Wang, R.-H., Kim, H.-S. & Deng, C.-X. RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat. Genet. 39, 1145–1150 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Hollenhorst, P.C., McIntosh, L.P. & Graves, B.J. Genomic and biochemical insights into the specificity of ETS transcription factors. Annu. Rev. Biochem. 80, 437–471 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wei, G.-H. Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo. EMBO J. 29, 2147–2160 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wilkie, A.O.M. et al. Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics 126, e391–e400 (2010).

    Article  PubMed  Google Scholar 

  14. Kan, S.-H. et al. Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis. Am. J. Hum. Genet. 70, 472–486 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lajeunie, E. et al. Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome. Eur. J. Hum. Genet. 14, 289–298 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Hammond, P. & Suttie, M.J. Large-scale phenotyping of 3D facial morphology. Hum. Mutat. 33, 817–825 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Papadaki, C. et al. Transcriptional repressor Erf determines extraembryonic ectoderm differentiation. Mol. Cell Biol. 27, 5201–5213 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mundlos, S. et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773–779 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Park, M.-H. et al. Differential expression patterns of Runx2 isoforms in cranial suture morphogenesis. J. Bone Miner. Res. 16, 885–892 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Komori, T. Signaling networks in RUNX2-dependent bone development. J. Cell Biochem. 112, 750–755 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Mefford, H.C. et al. Copy number variation analysis in single-suture craniosynostosis: multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis. Am. J. Med. Genet. 152A, 2203–2210 (2010).

    Article  PubMed  Google Scholar 

  22. Varvagiannis, K. et al. Pure de novo partial trisomy 6p in a girl with craniosynostosis. Am. J. Med. Genet. A. published online; 10.1002/ajmg.a.35727 (10 January 2013).

  23. Iseki, S., Wilkie, A.O.M. & Morriss-Kay, G.M. Fgfr1 and Fgfr2 have distinct differentation- and proliferation-related roles in the developing mouse skull vault. Development 126, 5611–5620 (1999).

    CAS  PubMed  Google Scholar 

  24. Hecht, J. et al. Detection of novel skeletogenesis target genes by comprehensive analysis of a Runx2−/− mouse model. Gene Expr. Patterns 7, 102–112 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Morriss-Kay, G.M. & Wilkie, A.O.M. Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. J. Anat. 207, 637–653 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Verykokakis, M., Papadaki, C., Vorgia, E., Le Gallic, L. & Mavrothalassitis, G. The RAS-dependent ERF control of cell proliferation and differentiation is mediated by c-Myc repression. J. Biol. Chem. 282, 30285–30294 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Bailey, T.L. et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 37, W202–W208 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dejosez, M. et al. Ronin/Hcf-1 binds to a hyperconserved enhancer element and regulates genes involved in the growth of embryonic stem cells. Genes Dev. 24, 1479–1484 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hollenhorst, P.C. et al. DNA specificity determinants associate with distinct transcription factor functions. PLoS Genet. 5, e1000778 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hollenhorst, P.C. et al. Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells. Genes Dev. 25, 2147–2157 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Goetz, T.L., Gu, T.L., Speck, N.A. & Graves, B.J. Auto-inhibition of Ets-1 is counteracted by DNA binding cooperativity with core-binding factor α2. Mol. Cell Biol. 20, 81–90 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hess, J., Porte, D., Munz, C. & Angel, P. AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone–dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1 composite element. J. Biol. Chem. 276, 20029–20038 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. D′Alonzo, R.C., Selvamurugan, N., Karsenty, G. & Partridge, N.C. Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation. J. Biol. Chem. 277, 816–822 (2002).

    Article  PubMed  Google Scholar 

  34. Allegra, M. et al. Semaphorin-7a reverses the ERF-induced inhibition of EMT in Ras-dependent mouse mammary epithelial cells. Mol. Biol. Cell 23, 3873–3881 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lou, Y. et al. A Runx2 threshold for the cleidocranial dysplasia phenotype. Hum. Mol. Genet. 18, 556–568 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Sumarsono, S.H. et al. Down′s syndrome–like skeletal abnormalities in Ets2 transgenic mice. Nature 379, 534–537 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Vary, C.P.H. et al. Involvement of Ets transcription factors and targets in osteoblast differentiation and matrix mineralization. Exp. Cell Res. 257, 213–222 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Little, G.H. et al. Genome-wide Runx2 occupancy in prostate cancer cells suggests a role in regulating secretion. Nucleic Acids Res. 40, 3538–3547 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Wai, P.Y. et al. Ets-1 and runx2 regulate transcription of a metastatic gene, osteopontin, in murine colorectal cancer cells. J. Biol. Chem. 281, 18973–18982 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Ge, C. et al. Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J. Biol. Chem. 284, 32533–32543 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Park, O.-J., Kim, H.-J., Woo, K.-M., Baek, J.-H. & Ryoo, H.-M. FGF2-activated ERK mitogen-activated protein kinase enhances Runx2 acetylation and stabilization. J. Biol. Chem. 285, 3568–3574 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Matsushita, T. et al. Extracellular signal–regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis. Mol. Cell Biol. 29, 5843–5857 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S.L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

    PubMed  PubMed Central  Google Scholar 

  44. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hammond, P. The use of 3D face shape modelling in dysmorphology. Arch. Dis. Child. 92, 1120–1126 (2007).

    Article  PubMed Central  Google Scholar 

  46. Watson, D.K. et al. The ERGB/Fli-1 gene: isolation and characterization of a new member of the family of human ETS transcription factors. Cell Growth Differ. 3, 705–713 (1992).

    CAS  PubMed  Google Scholar 

  47. Spyropoulos, D.D. et al. Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor. Mol. Cell Biol. 20, 5643–5652 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hogan, B. Manipulating the Mouse Embryo: a Laboratory Manual (Cold Spring Harbor Laboratory Press, Plainview, New York, 1994).

  49. Tallquist, M.D. & Soriano, P. Epiblast-restricted Cre expression in MORE mice: a tool to distinguish embryonic vs. extra-embryonic gene function. Genesis 26, 113–115 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Wilkinson, D.G. In-situ Hybridization: a Practical Approach (Oxford University Press, Oxford, 1992).

  51. Kowalczyk, M.S. et al. Intragenic enhancers act as alternative promoters. Mol. Cell 45, 447–458 (2012).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. Boehm, H. Care, C. Langman, J. Phipps and E. Sweeney for clinical assistance, L. Gregory, P. Piazza and staff at the High-Throughput Genomics facility at the Wellcome Trust Centre for Human Genetics for exome sequencing, C. Babbs, S. Butler, J. Frankland, C. Rode and T. Rostron for technical help, K. Kourouniotis for blastocyst injections and expert animal support, E. Giannoulatou for bioinformatics assistance, and B. Graves and P. Hollenhorst for discussions. We thank J. Heath (University of Birmingham), G. Schwabe (Charité University Hospital) and D. Rice (University of Helsinki) for the gifts of the Spp1, Runx2 and Bglap2 probes, respectively. This work was funded by the Greek Ministry of Education grants PYTHAGORAS II KA2092, PENED 03ED626, HERAKLEITOS II KA 3396 and SYNERGASIA 09SYN-11-902 to G.M., the NIHR Biomedical Research Centre, with funding from the Department of Health's NIHR Biomedical Research Centres funding scheme (S.J.L.K. and A.O.M.W.), the Oxford Craniofacial Unit Charitable Fund (V.P.S.), the Department of Health, UK, Quality, Improvement, Development and Initiative Scheme (QIDIS) (V.P.S.) and the Wellcome Trust (090532, S.J.L.K.; 093329, S.R.F.T. and A.O.M.W.). The views expressed in this publication are those of the authors and not necessarily those of the Department of Health, UK.

Author information

Author notes

  1. Elena Vorgia, Simon J McGowan, Ioanna Peraki and Aimée L Fenwick: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford,, Oxford, UK

    Stephen R F Twigg, Aimée L Fenwick, Vikram P Sharma & Andrew O M Wilkie

  2. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology–Hellas, Heraklion, Greece

    Elena Vorgia, Ioanna Peraki, Maryline Allegra & George Mavrothalassitis

  3. School of Medicine, University of Crete, Heraklion, Greece

    Elena Vorgia, Ioanna Peraki, Andreas Zaragkoulias & George Mavrothalassitis

  4. Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Simon J McGowan & Stephen Taylor

  5. Craniofacial Unit, Oxford University Hospitals National Health Service (NHS) Trust, Oxford, UK

    Vikram P Sharma, David Johnson, Steven A Wall & Andrew O M Wilkie

  6. National Institute for Health Research (NIHR) Biomedical Research Centre, Oxford and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Elham Sadighi Akha & Samantha J L Knight

  7. Molecular Genetics Laboratory, Oxford University Hospitals NHS Trust, Oxford, UK

    Helen Lord & Tracy Lester

  8. Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK

    Louise Izatt & Shehla N Mohammed

  9. South East of Scotland Clinical Genetics Service, NHS Lothian, Edinburgh, UK

    Anne K Lampe

  10. Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK

    Fiona J Stewart

  11. Département de Génétique, Assistance Publique–Hôpitaux de Paris (AP-HP)–Hôpital Robert Debré, Paris, France

    Alain Verloes

  12. North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK

    Louise C Wilson

  13. Department of Craniofacial Development and Stem Cell Biology, Dental Institute, King's College London, London, UK

    Chris Healy & Paul T Sharpe

  14. Molecular Medicine Unit, University College London (UCL) Institute of Child Health, London, UK

    Peter Hammond

  15. Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Jim Hughes

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  1. Stephen R F Twigg
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Contributions

S.R.F.T. designed and performed experiments and wrote the manuscript. M.A., I.P., A.L.F., E.V., A.Z., E.S.A., S.J.L.K., H.L. and T.L. performed experiments. S.J.M., J.H. and S.T. performed bioinformatic analyses. V.P.S. performed experiments and assessed patients. L.I., A.K.L., S.N.M., F.J.S., A.V., L.C.W., D.J. and S.A.W. identified and assessed patients. C.H. and P.T.S. performed and analyzed μCT scans. P.H. performed and analyzed three-dimensional facial imaging. G.M. conceived the project, designed experiments and wrote the manuscript. A.O.M.W. conceived the project, assessed patients, designed experiments and wrote the manuscript.

Corresponding authors

Correspondence to George Mavrothalassitis or Andrew O M Wilkie.

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Competing interests

The Foundation for Research and Technology–Hellas has filed a patent application with the UK Intellectual Property Office for the use of animals with decreased Erf activity in drug development for ossification defects.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–3, 9 and 10 and Supplementary Figures 1–10 (PDF 7508 kb)

Supplementary Table 4

ChIP-Seq targets identified with -FCS/+FCS >3 (non-TSS). (XLSX 339 kb)

Supplementary Table 5

ChIP-Seq targets identified with -FCS/+FCS >3 (TSS). (XLSX 250 kb)

Supplementary Table 6

Sequences near differentially bound ChIP-Seq targets (-FCS/+FCS >3; non-TSS) enriched for combinations of AP1, RUNX and ETS consensus binding sites – AP1. (XLSX 1153 kb)

Supplementary Table 7

Sequences near differentially bound ChIP-Seq targets (-FCS/+FCS >3; non-TSS) enriched for combinations of AP1, RUNX and ETS consensus binding sites – RUNX2. (XLSX 2863 kb)

Supplementary Table 8

Orthologous genes within 40 kb of ChIP-Seq peaks shared between datasets for Erf (-FCS/+FCS >3; non-TSS) in mouse embryonic fibroblasts (this work) and RUNX2 in human prostate carcinoma cells.38 (XLSX 23 kb)

Supplementary Movie 1

Animated morphs of faces of 4 ERF mutation-positive individuals from Family 1. (GIF 1693 kb)

Supplementary Movie 2

Animated morphs of faces of 2 ERF mutation-positive individuals from Family 4. (GIF 805 kb)

Supplementary Movie 3

Animated morphs of faces of 3 ERF mutation-positive individuals from Family 6. (GIF 1312 kb)

Supplementary Movie 4

Animated morphs of faces of 3 ERF mutation-positive individuals from Family 8. (GIF 1233 kb)

Supplementary Movie 5

Animated morphs of face of mutation-positive individual II-1 from Family 10. (GIF 338 kb)

Supplementary Movie 6

Animated morphs of faces of 3 ERF mutation-positive individuals from Family 11. (GIF 1171 kb)

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Twigg, S., Vorgia, E., McGowan, S. et al. Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. Nat Genet 45, 308–313 (2013). https://doi.org/10.1038/ng.2539

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