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In vivo genome-wide binding of Id2 to E2F4 target genes as part of a reversible program in mice liver

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Abstract

The inhibitor of differentiation Id2, a protein lacking the basic DNA-binding domain, is involved in the modulation of a number of biological processes. The molecular mechanisms explaining Id2 pleiotropic functions are poorly understood. Id2 and E2F4 are known to bind simultaneously to c-myc promoter. To study whether Id2 plays a global role on transcriptional regulation, we performed in vivo genome-wide ChIP/chip experiments for Id2 and E2F4 in adult mouse liver. An Id2-containing complex was bound to a common sequence downstream from the TSS on a subset of 442 E2F4 target genes mainly related to cell development and chromatin structure. We found a positive correlation between Id2 protein levels and the expression of E2F4/Id2 targets in fetal and adult liver. Id2 protein stability increased in fetal liver by interaction with USP1 de-ubiquitinating enzyme, which was induced during development. In adult liver, USP1 and Id2 levels dramatically decreased. In differentiated liver tissue, when Id2 concentration was low, E2F4/Id2 was bound to the same region as paused Pol II and target genes remained transcriptionally inactive. Conversely, in fetal liver when Id2 levels were increased, Id2 and Pol II were released from gene promoters and target genes up-regulated. During liver regeneration after partial hepatectomy, we obtained the same results as in fetal liver. Our results suggest that Id2 might be part of a reversible development-related program involved in the paused-ON/OFF state of Pol II on selected genes that would remain responsive to specific stimuli.

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References

  1. Murre C, McCaw PS, Vaessin H, Caudy M, Jan LY et al (1989) Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell 58:537–544

    Article  CAS  PubMed  Google Scholar 

  2. Benezra R, Davis RL, Lockshon D, Turner DL, Weintraub H (1990) The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell 61:49–59

    Article  CAS  PubMed  Google Scholar 

  3. Ruzinova MB, Benezra R (2003) Id proteins in development, cell cycle and cancer. Trends Cell Biol 13:410–418

    Article  CAS  PubMed  Google Scholar 

  4. Lasorella A, Uo T, Iavarone A (2001) Id proteins at the cross-road of development and cancer. Oncogene 20:8326–8333

    Article  CAS  PubMed  Google Scholar 

  5. Coma S, Amin DN, Shimizu A, Lasorella A, Iavarone A et al (2010) Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F. Cancer Res 70:3823–3832

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Norton JD, Atherton GT (1998) Coupling of cell growth control and apoptosis functions of Id proteins. Mol Cell Biol 18:2371–2381

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Matsumura ME, Lobe DR, McNamara CA (2002) Contribution of the helix-loop-helix factor Id2 to regulation of vascular smooth muscle cell proliferation. J Biol Chem 277:7293–7297

    Article  CAS  PubMed  Google Scholar 

  8. Rothschild G, Zhao X, Iavarone A, Lasorella A (2006) E Proteins and Id2 converge on p57Kip2 to regulate cell cycle in neural cells. Mol Cell Biol 26:4351–4361

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Rodríguez JL, Sandoval J, Serviddio G, Sastre J, Morante M et al (2006) Id2 leaves the chromatin of the E2F4-p130-controlled c-myc promoter during hepatocyte priming for liver regeneration. Biochem J 398:431–437

    Article  PubMed Central  PubMed  Google Scholar 

  10. Williams SA, Maecker HL, French DM, Liu J, Gregg A et al (2011) USP1 de-ubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma. Cell 146:918–930

    Article  CAS  PubMed  Google Scholar 

  11. Wang S, Sdrulla A, Johnson JE, Yokota Y, Barres BA (2001) A role for the helix-loop-helix protein Id2 in the control of oligodendrocyte development. Neuron 29:603–614

    Article  CAS  PubMed  Google Scholar 

  12. Bounpheng MA, Dimas JJ, Dodds SG, Christy BA (1999) Degradation of Id proteins by the ubiquitin-proteasome pathway. FASEB J 13:2257–2264

    CAS  PubMed  Google Scholar 

  13. Chen XS, Zhang YH, Cai QY, Yao ZX (2012) ID2: a negative transcription factor regulating oligodendroglia differentiation. J Neurosci Res 90:925–932

    Article  PubMed  Google Scholar 

  14. Torres L, Sandoval J, Penella E, Zaragozá R, García C et al (2009) In vivo GSH depletion induces c-myc expression by modulation of chromatin protein complexes. Free Radic Biol Med 46:1534–1542

    Article  CAS  PubMed  Google Scholar 

  15. van Oevelen C, Wang J, Asp P, Yan Q, Kaelin WG Jr et al (2008) A role for mammalian Sin3 in permanent gene silencing. Mol Cell 32:359–370

    Article  PubMed Central  PubMed  Google Scholar 

  16. Rayman JB, Takahashi Y, Indjeian VB, Dannenberg JH, Catchpole S et al (2002) E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex. Genes Dev 16:933–947

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Balciunaite E, Spektor A, Lents NH, Cam H, Te Riele H et al (2005) Pocket protein complexes are recruited to distinct targets in quiescent and proliferating cells. Mol Cell Biol 25:8166–8178

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Morello D, Fitzgerald MJ, Babinet C, Fausto N (1990) c-myc, c-fos, and c-jun regulation in the regenerating livers of normal and H-2 K/c-myc transgenic mice. Mol Cell Biol 10:3185–3193

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Torres L, Serna E, Bosch A, Zaragozá R, García C et al (2011) NF-ĸB as node for signal amplification during weaning. Cell Physiol Biochem 28:833–846

    Article  CAS  PubMed  Google Scholar 

  20. Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116–5121

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Sacilotto N, Espert A, Castillo J, Franco L, López-Rodas G (2011) Epigenetic transcriptional regulation of the growth arrest-specific gene 1 (Gas1) in hepatic cell proliferation at mononucleosomal resolution. PLoS ONE 6:e23318

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B (2008) Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 5:621–628

    Article  CAS  PubMed  Google Scholar 

  23. Otu HH, Naxerova K, Ho K, Can H, Nesbitt N et al (2007) Restoration of liver mass after injury requires proliferative and not embryonic transcriptional patterns. J Biol Chem 282:11197–11204

    Article  CAS  PubMed  Google Scholar 

  24. Mistry H, Hsieh G, Buhrlage SJ, Huang M, Park E et al (2013) Small-molecule inhibitors of USP1 target ID1 degradation in leukemic cells. Mol Cancer Ther 12:2651–2662

    Article  CAS  PubMed  Google Scholar 

  25. Samanta J, Kessler JA (2004) Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation. Development 131:4131–4142

    Article  CAS  PubMed  Google Scholar 

  26. Lasorella A, Iavarone A (2006) The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system. Proc Natl Acad Sci USA 103:4976–4981

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Garcia-Santisteban I, Zorroza K, Rodriguez JA (2012) Two nuclear localization signals in USP1 mediate nuclear import of the USP1/UAF1 complex. PLoS ONE 7:e38570

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Benson LJ, Gu Y, Yakovleva T, Tong K, Barrows C et al (2006) Modifications of H3 and H4 during chromatin replication, nucleosome assembly, and histone exchange. J Biol Chem 281:9287–9296

    Article  CAS  PubMed  Google Scholar 

  29. Ramirez-Carrozzi VR, Braas D, Bhatt DM, Cheng CS, Hong C et al (2009) A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138:114–128

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Core LJ, Waterfall JJ, Lis JT (2008) Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322:1845–1848

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Lee YF, Miller LD, Chan XB, Black MA, Pang B et al (2012) JMJD6 is a driver of cellular proliferation and motility and a marker of poor prognosis in breast cancer. Breast Cancer Res 14:R85

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Peters AH, O’Carroll D, Scherthan H, Mechtler K, Sauer S et al (2001) Loss of the Suv39 h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107:323–337

    Article  CAS  PubMed  Google Scholar 

  33. Gilchrist DA, Adelman K (2012) Coupling polymerase pausing and chromatin landscapes for precise regulation of transcription. Biochim Biophys Acta 1819:700–706

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Krumm A, Meulia T, Brunvand M, Groudine M (1992) The block to transcriptional elongation within the human c-myc gene is determined in the promoter-proximal region. Genes Dev 6:2201–2213

    Article  CAS  PubMed  Google Scholar 

  35. Kim JM, Parmar K, Huang M, Weinstock DM, Ruit CA et al (2009) Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev Cell 16(2):314–320

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Segal E, Fondufe-Mittendorf Y, Chen L, Thåström A, Field Y et al (2006) A genomic code for nucleosome positioning. Nature 442:772–778

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Gilchrist DA, Nechaev S, Lee C, Ghosh SK, Collins JB et al (2008) NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly. Genes Dev 22:1921–1933

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Guenther MG, Levine SS, Boyer LA, Jaenisch R, Young RA (2007) A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130:77–88

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Gilchrist DA, Dos Santos G, Fargo DC, Xie B, Gao Y et al (2010) Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation. Cell 143:540–551

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Coulouarn C, Derambure C, Lefebvre G, Daveau R, Hiron M et al (2005) Global gene repression in hepatocellular carcinoma and fetal liver, and suppression of dudulin-2 mRNA as a possible marker for the cirrhosis-to-tumor transition. J Hepatol 42:860–869

    Article  CAS  PubMed  Google Scholar 

  41. Li T, Wan B, Huang J, Zhang X (2010) Comparison of gene expression in hepatocellular carcinoma, liver development, and liver regeneration. Mol Genet Genomics 283:485–492

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by grants from Spanish government: PN I+D+I 2008-2011 [BFU2010-18253 to J.R.V] and ISCIII including FEDER funding [PI12/02394 to E.R.G-T], Consellería de Educación [GVPROMETEO 2010-075] and Fundación INCLIVA to RZ. T.A is the recipient of a pre-doctoral fellowship from Ministerio de Educación and I.F-V is funded by Consellería de Educación [GVPROMETEO 2010-075].

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Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular. Facultad de Medicina. Fundación Investigación Hospital Clínico-INCLIVA, Universidad de Valencia, Avda. Blasco Ibañez, 17, 46010, Valencia, Spain

    Ivan Ferrer-Vicens, Rosa Zaragozá, Concha García, Juan R. Viña, Luis Torres & Elena R. García-Trevijano

  2. Facultad de Ciencias Biológicas. Fundación Investigación Hospital Clínico-INCLIVA, Universidad de Valencia, Avda. Blasco Ibañez, 17, 46010, Valencia, Spain

    Ángela L. Riffo‐Campos & Gerardo López-Rodas

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  1. Ivan Ferrer-Vicens
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  2. Ángela L. Riffo‐Campos
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  3. Rosa Zaragozá
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  8. Elena R. García-Trevijano
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Correspondence to Elena R. García-Trevijano.

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Ferrer-Vicens, I., Riffo‐Campos, Á.L., Zaragozá, R. et al. In vivo genome-wide binding of Id2 to E2F4 target genes as part of a reversible program in mice liver. Cell. Mol. Life Sci. 71, 3583–3597 (2014). https://doi.org/10.1007/s00018-014-1588-1

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  • DOI: https://doi.org/10.1007/s00018-014-1588-1

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