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Gene Expression in the Third Dimension: The ECM-nucleus Connection

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Decades ago, we and others proposed that the dynamic interplay between a cell and its surrounding environment dictates cell phenotype and tissue structure. Whereas much has been discovered about the effects of extracellular matrix molecules on cell growth and tissue-specific gene expression, the nuclear mechanisms through which these molecules promote these physiological events remain unknown. Using mammary epithelial cells as a model, the purpose of this review is to discuss how the extracellular matrix influences nuclear structure and function in a three-dimensional context to promote epithelial morphogenesis and function in the mammary gland.

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Abbreviations

ECM:

extracellular matrix

LrECM:

laminin-rich extracellular matrix

CTs:

chromosome territories

ES:

embyronic stem

MEC:

mammary epithelial cell

Col-IV:

collagen type IV

Col-I:

collagen type I

LN1:

laminin type I

LN5:

laminin type V

BM:

basement membrane

ILK:

integrin-linked kinase

PrlR:

prolactin receptor

STAT5:

signal transducer and activator of transcription 5

KASH:

Klarsicht, ANC-1, Syne Homology

SUN:

Sad1p, UNC-84

Jak2:

Just-Another-Kinase 2

BCE-1:

bovine β-casein ECM response element

NuMA:

nuclear mitotic apparatus

PML:

promyelocytic leukemia

References

  1. Getzenberg RH, Pienta KJ, Ward WS, Coffey DS. Nuclear structure and the three-dimensional organization of DNA. J Cell Biochem. 1991;47(4):289–99.

    Article  PubMed  CAS  Google Scholar 

  2. Hager GL, Nagaich AK, Johnson TA, Walker DA, John S. Dynamics of nuclear receptor movement and transcription. Biochim Biophys Acta. 2004;1677(1–3):46–51.

    PubMed  CAS  Google Scholar 

  3. Misteli T. Concepts in nuclear architecture. Bioessays. 2005;27(5):477–87.

    Article  PubMed  CAS  Google Scholar 

  4. Cremer T, Cremer M, Dietzel S, Muller S, Solovei I, Fakan S. Chromosome territories-a functional nuclear landscape. Curr Opin Cell Biol. 2006;18(3):307–16.

    Article  PubMed  CAS  Google Scholar 

  5. Mahy NL, Perry PE, Bickmore WA. Gene density and transcription influence the localization of chromatin outside of chromosome territories detectable by FISH. J Cell Biol. 2002;159(5):753–63.

    Article  PubMed  CAS  Google Scholar 

  6. Scheuermann MO, Tajbakhsh J, Kurz A, Saracoglu K, Eils R, Lichter P. Topology of genes and nontranscribed sequences in human interphase nuclei. Exp Cell Res. 2004;301(2):266–79.

    Article  PubMed  CAS  Google Scholar 

  7. Tajbakhsh J, Luz H, Bornfleth H, Lampel S, Cremer C, Lichter P. Spatial distribution of GC- and AT-rich DNA sequences within human chromosome territories. Exp Cell Res. 2000;255(2):229–37.

    Article  PubMed  CAS  Google Scholar 

  8. Nickerson J. Experimental observations of a nuclear matrix. J Cell Sci. 2001;114(Pt 3):463–74.

    PubMed  CAS  Google Scholar 

  9. Zaidi SK, Young DW, Javed A, Pratap J, Montecino M, van Wijnen A, et al. Nuclear microenvironments in biological control and cancer. Nat Rev Cancer. 2007;7(6):454–63.

    Article  PubMed  CAS  Google Scholar 

  10. Lamond AI, Earnshaw WC. Structure and function in the nucleus. Science. 1998;280(5363):547–53.

    Article  PubMed  CAS  Google Scholar 

  11. Lamond AI, Spector DL. Nuclear speckles: a model for nuclear organelles. Nat Rev Mol Cell Biol. 2003;4(8):605–12.

    Article  PubMed  CAS  Google Scholar 

  12. Spector DL. Nuclear domains. J Cell Sci. 2001;114(Pt 16):2891–3.

    PubMed  CAS  Google Scholar 

  13. Efroni S, Duttagupta R, Cheng J, Dehghani H, Hoeppner DJ, Dash C, et al. Global transcription in pluripotent embryonic stem cells. Cell Stem Cell. 2008;2(5):437–47.

    Article  PubMed  CAS  Google Scholar 

  14. Lee JH, Hart SR, Skalnik DG. Histone deacetylase activity is required for embryonic stem cell differentiation. Genesis. 2004;38(1):32–8.

    Article  PubMed  CAS  Google Scholar 

  15. Meshorer E, Yellajoshula D, George E, Scambler PJ, Brown DT, Misteli T. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell. 2006;10(1):105–16.

    Article  PubMed  CAS  Google Scholar 

  16. Hager GL, Elbi C, Becker M. Protein dynamics in the nuclear compartment. Curr Opin Genet Dev. 2002;12(2):137–41.

    Article  PubMed  CAS  Google Scholar 

  17. Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression? J Theor Biol. 1982;99(1):31–68.

    Article  PubMed  CAS  Google Scholar 

  18. Ferguson JE, Schor AM, Howell A, Ferguson MW. Changes in the extracellular matrix of the normal human breast during the menstrual cycle. Cell Tissue Res. 1992;268(1):167–77.

    Article  PubMed  CAS  Google Scholar 

  19. Keely PJ, Wu JE, Santoro SA. The spatial and temporal expression of the alpha 2 beta 1 integrin and its ligands, collagen I, collagen IV, and laminin, suggest important roles in mouse mammary morphogenesis. Differentiation. 1995;59(1):1–13.

    Article  PubMed  CAS  Google Scholar 

  20. Stoeckelhuber M, Stumpf P, Hoefter EA, Welsch U. Proteoglycan-collagen associations in the non-lactating human breast connective tissue during the menstrual cycle. Histochem Cell Biol. 2002;118(3):221–30.

    PubMed  CAS  Google Scholar 

  21. Woodward TL, Mienaltowski AS, Modi RR, Bennett JM, Haslam SZ. Fibronectin and the alpha(5)beta(1) integrin are under developmental and ovarian steroid regulation in the normal mouse mammary gland. Endocrinology. 2001;142(7):3214–22.

    Article  PubMed  CAS  Google Scholar 

  22. Russo J, Russo IH. DNA labeling index and structure of the rat mammary gland as determinants of its susceptibility to carcinogenesis. J Natl Cancer Inst. 1978;61(6):1451–9.

    PubMed  CAS  Google Scholar 

  23. Williams JM, Daniel CW. Mammary ductal elongation: differentiation of myoepithelium and basal lamina during branching morphogenesis. Dev Biol. 1983;97(2):274–90.

    Article  PubMed  CAS  Google Scholar 

  24. Klinowska TC, Soriano JV, Edwards GM, Oliver JM, Valentijn AJ, Montesano R, et al. Laminin and beta1 integrins are crucial for normal mammary gland development in the mouse. Dev Biol. 1999;215(1):13–32.

    Article  PubMed  CAS  Google Scholar 

  25. Prince JM, Klinowska TC, Marshman E, Lowe ET, Mayer U, Miner J, et al. Cell-matrix interactions during development and apoptosis of the mouse mammary gland in vivo. Dev Dyn. 2002;223(4):497–516.

    Article  PubMed  CAS  Google Scholar 

  26. Ghajar CM, Bissell MJ. Extracellular matrix control of mammary gland morphogenesis and tumorigenesis: insights from imaging. Histochem Cell Biol. 2008;130(6):1105–18.

    Article  PubMed  CAS  Google Scholar 

  27. Michalopoulos G. Pitot HC. Primary culture of parenchymal liver cells on collagen membranes Morphological and biochemical observations Exp Cell Res. 1975;94(1):70–8.

    CAS  Google Scholar 

  28. Emerman JT, Burwen SJ, Pitelka DR. Substrate properties influencing ultrastructural differentiation of mammary epithelial cells in culture. Tissue Cell. 1979;11(1):109–19.

    Article  PubMed  CAS  Google Scholar 

  29. Emerman JT, Pitelka DR. Maintenance and induction of morphological differentiation in dissociated mammary epithelium on floating collagen membranes. In Vitro. 1977;13(5):316–28.

    Article  PubMed  CAS  Google Scholar 

  30. Lee EY, Lee WH, Kaetzel CS, Parry G, Bissell MJ. Interaction of mouse mammary epithelial cells with collagen substrata: regulation of casein gene expression and secretion. Proc Natl Acad Sci U S A. 1985;82(5):1419–23.

    Article  PubMed  CAS  Google Scholar 

  31. Lee EY, Parry G, Bissell MJ. Modulation of secreted proteins of mouse mammary epithelial cells by the collagenous substrata. J Cell Biol. 1984;98(1):146–55.

    Article  PubMed  CAS  Google Scholar 

  32. Streuli CH, Bissell MJ. Expression of extracellular matrix components is regulated by substratum. J Cell Biol. 1990;110(4):1405–15.

    Article  PubMed  CAS  Google Scholar 

  33. Streuli CH, Schmidhauser C, Bailey N, Yurchenco P, Skubitz AP, Roskelley C, et al. Laminin mediates tissue-specific gene expression in mammary epithelia. J Cell Biol. 1995;129(3):591–603.

    Article  PubMed  CAS  Google Scholar 

  34. Roskelley CD, Desprez PY, Bissell MJ. Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transduction. Proc Natl Acad Sci U S A. 1994;91(26):12378–82.

    Article  PubMed  CAS  Google Scholar 

  35. Muschler J, Lochter A, Roskelley CD, Yurchenco P, Bissell MJ. Division of labor among the alpha6beta4 integrin, beta1 integrins, and an E3 laminin receptor to signal morphogenesis and beta-casein expression in mammary epithelial cells. Mol Biol Cell. 1999;10(9):2817–28.

    PubMed  CAS  Google Scholar 

  36. Weir ML, Oppizzi ML, Henry MD, Onishi A, Campbell KP, Bissell MJ, et al. Dystroglycan loss disrupts polarity and beta-casein induction in mammary epithelial cells by perturbing laminin anchoring. J Cell Sci. 2006;119(Pt 19):4047–58.

    Article  PubMed  CAS  Google Scholar 

  37. Henry MD, Campbell KP. A role for dystroglycan in basement membrane assembly. Cell. 1998;95(6):859–70.

    Article  PubMed  CAS  Google Scholar 

  38. Akhtar N, Marlow R, Lambert E, Schatzmann F, Lowe ET, Cheung J, et al. Molecular dissection of integrin signalling proteins in the control of mammary epithelial development and differentiation. Development. 2009;136(6):1019–27.

    Article  PubMed  CAS  Google Scholar 

  39. Myers CA, Schmidhauser C, Mellentin-Michelotti J, Fragoso G, Roskelley CD, Casperson G, et al. Characterization of BCE-1, a transcriptional enhancer regulated by prolactin and extracellular matrix and modulated by the state of histone acetylation. Mol Cell Biol. 1998;18(4):2184–95.

    PubMed  CAS  Google Scholar 

  40. Wakao H, Gouilleux F, Groner B. Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. EMBO J. 1994;13(9):2182–91.

    PubMed  CAS  Google Scholar 

  41. Xu R, Nelson CM, Muschler JL, Veiseh M, Vonderhaar BK, Bissell MJ. Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary-specific function. J Cell Biol. 2009;184(1):57–66.

    Article  PubMed  CAS  Google Scholar 

  42. Sheetz MP. Cell control by membrane-cytoskeleton adhesion. Nat Rev Mol Cell Biol. 2001;2(5):392–6.

    Article  PubMed  CAS  Google Scholar 

  43. Wiesner S, Legate KR, Fassler R. Integrin-actin interactions. Cell Mol Life Sci. 2005;62(10):1081–99.

    Article  PubMed  CAS  Google Scholar 

  44. Fridkin A, Penkner A, Jantsch V, Gruenbaum Y. SUN-domain and KASH-domain proteins during development, meiosis and disease. Cell Mol Life Sci. 2009;66(9):1518–33.

    Article  PubMed  CAS  Google Scholar 

  45. Starr DA, Fischer JA. KASH ’n Karry: the KASH domain family of cargo-specific cytoskeletal adaptor proteins. Bioessays. 2005;27(11):1136–46.

    Article  PubMed  CAS  Google Scholar 

  46. Tzur YB, Wilson KL, Gruenbaum Y. SUN-domain proteins: ‘Velcro’ that links the nucleoskeleton to the cytoskeleton. Nat Rev Mol Cell Biol. 2006;7(10):782–8.

    Article  PubMed  CAS  Google Scholar 

  47. Dahl KN, Ribeiro AJ, Lammerding J. Nuclear shape, mechanics, and mechanotransduction. Circ Res. 2008;102(11):1307–18.

    Article  PubMed  CAS  Google Scholar 

  48. Maniotis AJ, Chen CS, Ingber DE. Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure. Proc Natl Acad Sci U S A. 1997;94(3):849–54.

    Article  PubMed  CAS  Google Scholar 

  49. Lammerding J, Schulze PC, Takahashi T, Kozlov S, Sullivan T, Kamm RD, et al. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest. 2004;113(3):370–8.

    PubMed  CAS  Google Scholar 

  50. Weaver VM, Petersen OW, Wang F, Larabell CA, Briand P, Damsky C, et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol. 1997;137(1):231–45.

    Article  PubMed  CAS  Google Scholar 

  51. Zoubiane GS, Valentijn A, Lowe ET, Akhtar N, Bagley S, Gilmore AP, et al. A role for the cytoskeleton in prolactin-dependent mammary epithelial cell differentiation. J Cell Sci. 2004;117(Pt 2):271–80.

    Article  PubMed  CAS  Google Scholar 

  52. Alcaraz J, Xu R, Mori H, Nelson CM, Mroue R, Spencer VA, et al. Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia. EMBO J. 2008;27(21):2829–38.

    Article  PubMed  CAS  Google Scholar 

  53. Spencer VA, Xu R, Bissell MJ. Extracellular matrix, nuclear and chromatin structure, and gene expression in normal tissues and malignant tumors: a work in progress. Adv Cancer Res. 2007;97:275–94.

    Article  PubMed  CAS  Google Scholar 

  54. Fournier MV, Martin KJ, Kenny PA, Xhaja K, Bosch I, Yaswen P, et al. Gene expression signature in organized and growth-arrested mammary acini predicts good outcome in breast cancer. Cancer Res. 2006;66(14):7095–102.

    Article  PubMed  CAS  Google Scholar 

  55. Petersen OW, Ronnov-Jessen L, Howlett AR, Bissell MJ. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc Natl Acad Sci U S A. 1992;89(19):9064–8.

    Article  PubMed  CAS  Google Scholar 

  56. Le Beyec J, Xu R, Lee SY, Nelson CM, Rizki A, Alcaraz J, et al. Cell shape regulates global histone acetylation in human mammary epithelial cells. Exp Cell Res. 2007;313(14):3066–75.

    Article  PubMed  CAS  Google Scholar 

  57. Maniotis AJ, Valyi-Nagy K, Karavitis J, Moses J, Boddipali V, Wang Y, et al. Chromatin organization measured by AluI restriction enzyme changes with malignancy and is regulated by the extracellular matrix and the cytoskeleton. Am J Pathol. 2005;166(4):1187–203.

    PubMed  CAS  Google Scholar 

  58. Plachot C, Lelievre SA. DNA methylation control of tissue polarity and cellular differentiation in the mammary epithelium. Exp Cell Res. 2004;298(1):122–32.

    Article  PubMed  CAS  Google Scholar 

  59. Kaminker P, Plachot C, Kim SH, Chung P, Crippen D, Petersen OW, et al. Higher-order nuclear organization in growth arrest of human mammary epithelial cells: a novel role for telomere-associated protein TIN2. J Cell Sci. 2005;118(Pt 6):1321–30.

    Article  PubMed  CAS  Google Scholar 

  60. Knowles DW, Sudar D, Bator-Kelly C, Bissell MJ, Lelievre SA. Automated local bright feature image analysis of nuclear protein distribution identifies changes in tissue phenotype. Proc Natl Acad Sci U S A. 2006;103(12):4445–50.

    Article  PubMed  CAS  Google Scholar 

  61. Lelievre SA, Weaver VM, Nickerson JA, Larabell CA, Bhaumik A, Petersen OW, et al. Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus. Proc Natl Acad Sci U S A. 1998;95(25):14711–6.

    Article  PubMed  CAS  Google Scholar 

  62. Boisvert FM, Hendzel MJ, Bazett-Jones DP. Promyelocytic leukemia (PML) nuclear bodies are protein structures that do not accumulate RNA. J Cell Biol. 2000;148(2):283–92.

    Article  PubMed  CAS  Google Scholar 

  63. Negorev D, Maul GG. Cellular proteins localized at and interacting within ND10/PML nuclear bodies/PODs suggest functions of a nuclear depot. Oncogene. 2001;20(49):7234–42.

    Article  PubMed  CAS  Google Scholar 

  64. Torok D, Ching RW, Bazett-Jones DP. PML nuclear bodies as sites of epigenetic regulation. Front Biosci. 2009;14:1325–36.

    Article  PubMed  CAS  Google Scholar 

  65. Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP. The mechanisms of PML-nuclear body formation. Mol Cell. 2006;24(3):331–9.

    Article  PubMed  CAS  Google Scholar 

  66. Lin DY, Huang YS, Jeng JC, Kuo HY, Chang CC, Chao TT, et al. Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol Cell. 2006;24(3):341–54.

    Article  PubMed  CAS  Google Scholar 

  67. Takahashi H, Hatakeyama S, Saitoh H, Nakayama KI. Noncovalent SUMO-1 binding activity of thymine DNA glycosylase (TDG) is required for its SUMO-1 modification and colocalization with the promyelocytic leukemia protein. J Biol Chem. 2005;280(7):5611–21.

    Article  PubMed  CAS  Google Scholar 

  68. Sternsdorf T, Jensen K, Freemont PS. Sumo. Curr Biol. 2003;13(7):R258–9.

    Article  PubMed  CAS  Google Scholar 

  69. Bissell MJ, Weaver VM, Lelievre SA, Wang F, Petersen OW, Schmeichel KL. Tissue structure, nuclear organization, and gene expression in normal and malignant breast. Cancer Res. 1999;59(7 Suppl):1757s–64s. discussion 1763s–4s.

    CAS  Google Scholar 

  70. Lin CQ, Bissell MJ. Multi-faceted regulation of cell differentiation by extracellular matrix. FASEB J. 1993;7(9):737–43.

    PubMed  CAS  Google Scholar 

  71. Roskelley CD, Srebrow A, Bissell MJ. A hierarchy of ECM-mediated signalling regulates tissue-specific gene expression. Curr Opin Cell Biol. 1995;7(5):736–47.

    Article  PubMed  CAS  Google Scholar 

  72. Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression. Nat Rev Cancer. 2009;9(2):108–22.

    Article  PubMed  CAS  Google Scholar 

  73. Close MJ, Howlett AR, Roskelley CD, Desprez PY, Bailey N, Rowning B, et al. Lactoferrin expression in mammary epithelial cells is mediated by changes in cell shape and actin cytoskeleton. J Cell Sci. 1997;110(Pt 22):2861–71.

    PubMed  CAS  Google Scholar 

  74. Gouilleux F, Wakao H, Mundt M, Groner B. Prolactin induces phosphorylation of Tyr694 of Stat5 (MGF), a prerequisite for DNA binding and induction of transcription. Embo J. 1994;13(18):4361–9.

    PubMed  CAS  Google Scholar 

  75. Xu R, Spencer VA, Bissell MJ. Extracellular matrix-regulated gene expression requires cooperation of SWI/SNF and transcription factors. J Biol Chem. 2007;282(20):14992–9.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Rana Mroue and Joni Mott for their constructive comments in the writing of this manuscript. This work was supported by grants from the U.S. Department of Energy, the Office of Biological and Environmental Research (contract no. DE-AC02-05CH1123), a Low Dose Radiation Program and a Distinguished Fellow Award from the Office of Health and Environmental Research Health Effects Division (contract no. 03-76SF00098) to MJB, the National Cancer Institute (awards R01CA064786, U54CA126552 and U54CA112970 to MJB and R01CA057621 to MJB and Zena Werb), the U.S. Department of Defense Medical and Materiel Command innovator award (contract no.W81XWH0810736 and W81XWH0510338) to MJB, and postdoctoral fellowships W81XWH0410581 to V.A.S and DAMD17-02-1-0441 to R.X., and a post-doctoral fellowship to V.A.S. from the Canadian Institutes of Health Research.

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  1. Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, MS 977R225A, Berkeley, CA, 94720, USA

    Virginia A. Spencer, Ren Xu & Mina J. Bissell

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  1. Virginia A. Spencer
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  2. Ren Xu
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Correspondence to Virginia A. Spencer or Mina J. Bissell.

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Spencer, V.A., Xu, R. & Bissell, M.J. Gene Expression in the Third Dimension: The ECM-nucleus Connection. J Mammary Gland Biol Neoplasia 15, 65–71 (2010). https://doi.org/10.1007/s10911-010-9163-3

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