The Role of ATP-dependent Chromatin Remodeling in the Control of Epidermal Differentiation and Skin Stem Cell Activity

  • Gitali Ganguli-Indra
  • Arup K. IndraEmail author
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


ATP-dependent chromatin remodeling complexes are involved in chromatin remodeling thereby controlling gene expression. These multi-subunit containing complexes contain an ATPase of the SNF2 family that hydrolyzes ATP in order to modify or reshape histone-DNA interactions within nucleosomes. Several subfamilies of the SNF2 family have been identified in different species based on the status of their catalytic ATPase subunit. All of the SNF2 subfamily members, including SWI2/SNF2 (BRG1/BRM), ISWI and CHD/Mi-2β, play critical roles in the maintenance of epidermal homeostasis. The BRG1 chromatin remodeler is required for maintenance of bulge stem cells, hair cycling, normal skin homeostasis, and repair and regeneration processes. ACTL6a (actin-like 6a) modulates the SWI/SNF complex to suppress differentiation in the epidermis. Realignment of the epidermal differentiation complex (EDC) locus, which occurs before activation of EDC genes that drive keratinocyte terminal differentiation, is coordinated by p63 by directly regulating the expression of BRG1. The combined effects of p63 and BRG1 control higher order chromatin remodeling, 3D-genomic organization and efficient expression of EDC genes in epidermal precursor cells during epidermal morphogenesis. BRG1 also suppresses p27kip1, allowing self-renewal of hair follicle bulge cells, and recruits the transcription factor NF-kB, which in turn activates Shh in matrix cells, promoting proliferation. Finally, Shh signaling through Gli activates BRG1 in bulge cells. Hence, BRG1 is necessary for Shh expression in both matrix and bulge compartments, and for hair regeneration and skin repair post-wounding. Mice with deletion of Mi-2β of the SNF2 family in the epidermis die perinatally and display severalphenotypes that differ between dorsal and ventral skin, suggesting spatio-temporal control of gene expression by Mi-2β in the epidermis. Mi-2β is also important for hair follicle morphogenesis and is necessary to reprogram epidermal basal cells to a hair follicle fate. Non-melanoma skin cancers in humans display mutations in the Brm gene following ultraviolet (UV) irradiation, and BRM normally protects epidermal cells from UV irradiation-induced hyper-proliferation, even in the presence of a partial loss of p53, thereby establishing its role as a tumor suppressor.


ATP-dependent chromatin remodeling complexes SWI2/SNF2 stem cells epidermis hair follicles 3D-genomic organization wound healing EDC BRG1/BRM 



Actin-like 6a


Apical ectodermal ridge


Adenosine tri-phosphate


ATP-dependent chromatin remodeling


BRG1/BRM associated factors

C elegans



Epidermal differentiation complex


Epidermal permeability barrier


Hair follicle;


Hair follicle stem cells


Imitation SWI2


Kruppel-like factor 4


Sucrose Non Fermentation


Mating type Switching 2


  1. 1.
    Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Annu Rev Biochem. 2009;78:273–304. Epub 2009/04/10. PubMed PMID: 19355820.CrossRefPubMedGoogle Scholar
  2. 2.
    Stern M, Jensen R, Herskowitz I. Five SWI genes are required for expression of the HO gene in yeast. J Mol Biol. 1984;178(4):853–68. Epub 1984/10/05. PubMed PMID: 6436497.CrossRefPubMedGoogle Scholar
  3. 3.
    Eberharter A, Becker PB. ATP-dependent nucleosome remodelling: factors and functions. J Cell Sci. 2004;117(Pt 17):3707–11. Epub 2004/08/03. PubMed PMID: 15286171.CrossRefPubMedGoogle Scholar
  4. 4.
    Wu JI, Lessard J, Crabtree GR. Understanding the words of chromatin regulation. Cell. 2009;136(2):200–6. Epub 2009/01/27. PubMed PMID: 19167321; PubMed Central PMCID: PMC2770578.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kalinin AE, Kajava AV, Steinert PM. Epithelial barrier function: assembly and structural features of the cornified cell envelope. BioEssays. 2002;24(9):789–800. Epub 2002/09/05. PubMed PMID: 12210515.CrossRefPubMedGoogle Scholar
  6. 6.
    Kadam S, Emerson BM. Transcriptional specificity of human SWI/SNF BRG1 and BRM chromatin remodeling complexes. Mol Cell. 2003;11(2):377–89. Epub 2003/03/07. PubMed PMID: 12620226.CrossRefPubMedGoogle Scholar
  7. 7.
    Reyes JC, Barra J, Muchardt C, Camus A, Babinet C, Yaniv M. Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha). EMBO J. 1998;17(23):6979–91. Epub 1998/12/08. PubMed PMID: 9843504; PubMed Central PMCID: PMC1171046.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bultman S, Gebuhr T, Yee D, La Mantia C, Nicholson J, Gilliam A, Randazzo F, Metzger D, Chambon P, Crabtree G, Magnuson T. A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. Mol Cell. 2000;6(6):1287–95. Epub 2001/02/13. PubMed PMID: 11163203.CrossRefPubMedGoogle Scholar
  9. 9.
    Li M, Chiba H, Warot X, Messaddeq N, Gerard C, Chambon P, Metzger D. RXR-alpha ablation in skin keratinocytes results in alopecia and epidermal alterations. Development. 2001;128(5):675–88. Epub 2001/02/15. PubMed PMID: 11171393.PubMedGoogle Scholar
  10. 10.
    Li M, Indra AK, Warot X, Brocard J, Messaddeq N, Kato S, Metzger D, Chambon P. Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature. 2000;407(6804):633–6. Epub 2000/10/18. PubMed PMID: 11034212.CrossRefPubMedGoogle Scholar
  11. 11.
    Vassar R, Rosenberg M, Ross S, Tyner A, Fuchs E. Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice. Proc Natl Acad Sci U S A. 1989;86(5):1563–7. Epub 1989/03/01. PubMed PMID: 2466292; PubMed Central PMCID: PMC286738.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Indra AK, Li M, Brocard J, Warot X, Bornert JM, Gerard C, Messaddeq N, Chambon P, Metzger D. Targeted somatic mutagenesis in mouse epidermis. Horm Res. 2000;54(5–6):296–300. Epub 2001/10/12. doi: 53275. PubMed PMID: 11595821.PubMedGoogle Scholar
  13. 13.
    Indra AK, Dupe V, Bornert JM, Messaddeq N, Yaniv M, Mark M, Chambon P, Metzger D. Temporally controlled targeted somatic mutagenesis in embryonic surface ectoderm and fetal epidermal keratinocytes unveils two distinct developmental functions of BRG1 in limb morphogenesis and skin barrier formation. Development. 2005;132(20):4533–44. Epub 2005/09/30. PubMed PMID: 16192310.CrossRefPubMedGoogle Scholar
  14. 14.
    Kaufman MH, BLB J. The anatomical basis of mouse development. San Diego: Academic; 1999. 291 p.Google Scholar
  15. 15.
    Byrne C, Hardman M, Nield K. Covering the limb – formation of the integument. J Anat. 2003;202(1):113–23. Epub 2003/02/18. PubMed PMID: 12587926; PubMed Central PMCID: PMC1571060.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sumi-Ichinose C, Ichinose H, Metzger D, Chambon P. SNF2beta-BRG1 is essential for the viability of F9 murine embryonal carcinoma cells. Mol Cell Biol. 1997;17(10):5976–86. Epub 1997/10/07. PubMed PMID: 9315656; PubMed Central PMCID: PMC232446.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Bao X, Tang J, Lopez-Pajares V, Tao S, Qu K, Crabtree GR, Khavari PA. ACTL6a enforces the epidermal progenitor state by suppressing SWI/SNF-dependent induction of KLF4. Cell Stem Cell. 2013;12(2):193–203. Epub 2013/02/12. PubMed PMID: 23395444; PubMed Central PMCID: PMC3661004.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Park J, Wood MA, Cole MD. BAF53 forms distinct nuclear complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation. Mol Cell Biol. 2002;22(5):1307–16. Epub 2002/02/13. PubMed PMID: 11839798; PubMed Central PMCID: PMC134713.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tea JS, Luo L. The chromatin remodeling factor Bap55 functions through the TIP60 complex to regulate olfactory projection neuron dendrite targeting. Neural Dev. 2011;6:5. Epub 2011/02/03. PubMed PMID: 21284845; PubMed Central PMCID: PMC3038883.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Zhao K, Wang W, Rando OJ, Xue Y, Swiderek K, Kuo A, Crabtree GR. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell. 1998;95(5):625–36. Epub 1998/12/09. PubMed PMID: 9845365.CrossRefPubMedGoogle Scholar
  21. 21.
    Mulder KW, Wang X, Escriu C, Ito Y, Schwarz RF, Gillis J, Sirokmany G, Donati G, Uribe-Lewis S, Pavlidis P, Murrell A, Markowetz F, Watt FM. Diverse epigenetic strategies interact to control epidermal differentiation. Nat Cell Biol. 2012;14(7):753–63. Epub 2012/06/26. PubMed PMID: 22729083.CrossRefPubMedGoogle Scholar
  22. 22.
    Bao Y. Chromatin response to DNA double-strand break damage. Epigenomics. 2011;3(3):307–21. Epub 2011/11/30. PubMed PMID: 22122340.CrossRefPubMedGoogle Scholar
  23. 23.
    Kim J, Sif S, Jones B, Jackson A, Koipally J, Heller E, Winandy S, Viel A, Sawyer A, Ikeda T, Kingston R, Georgopoulos K. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity. 1999;10(3):345–55. Epub 1999/04/16. PubMed PMID: 10204490.CrossRefPubMedGoogle Scholar
  24. 24.
    Kashiwagi M, Morgan BA, Georgopoulos K. The chromatin remodeler Mi-2beta is required for establishment of the basal epidermis and normal differentiation of its progeny. Development. 2007;134(8):1571–82. Epub 2007/03/16. PubMed PMID: 17360773.CrossRefPubMedGoogle Scholar
  25. 25.
    Botchkarev VA, Gdula MR, Mardaryev AN, Sharov AA, Fessing MY. Epigenetic regulation of gene expression in keratinocytes. J Invest Dermatol. 2012;132(11):2505–21. Epub 2012/07/06. PubMed PMID: 22763788; PubMed Central PMCID: PMC3650472.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Cremer T, Cremer M. Chromosome territories. In: Misteli T, Spector D, editors. The Nucleus. New York: Cold Spring Harbor Laboratory Press; 2011. p. 93–114.Google Scholar
  27. 27.
    Sanyal A, Bau D, Marti-Renom MA, Dekker J. Chromatin globules: a common motif of higher order chromosome structure? Curr Opin Cell Biol. 2011;23(3):325–31. Epub 2011/04/15. PubMed PMID: 21489772; PubMed Central PMCID: PMC3109114.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Koster MI, Roop DR. Mechanisms regulating epithelial stratification. Annu Rev Cell Dev Biol. 2007;23:93–113. Epub 2007/05/11. PubMed PMID: 17489688.CrossRefPubMedGoogle Scholar
  29. 29.
    Truong AB, Khavari PA. Control of keratinocyte proliferation and differentiation by p63. Cell Cycle. 2007;6(3):295–9. Epub 2007/02/01. PubMed PMID: 17264679.CrossRefPubMedGoogle Scholar
  30. 30.
    Mardaryev AN, Gdula MR, Yarker JL, Emelianov VU, Poterlowicz K, Sharov AA, Sharova TY, Scarpa JA, Joffe B, Solovei I, Chambon P, Botchkarev VA, Fessing MY. p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells. Development. 2014;141(1):101–11. Epub 2013/12/19. PubMed PMID: 24346698; PubMed Central PMCID: PMC3865752.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lopez-Pajares V, Qu K, Zhang J, Webster DE, Barajas BC, Siprashvili Z, Zarnegar BJ, Boxer LD, Rios EJ, Tao S, Kretz M, Khavari PA. A LncRNA-MAF:MAFB transcription factor network regulates epidermal differentiation. Dev Cell. 2015;32(6):693–706. PubMed PMID: 25805135; PubMed Central PMCID: PMCPMC4456036.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Cavazza A, Miccio A, Romano O, Petiti L, Malagoli Tagliazucchi G, Peano C, Severgnini M, Rizzi E, De Bellis G, Bicciato S, Mavilio F. Dynamic transcriptional and epigenetic regulation of human epidermal keratinocyte differentiation. Stem Cell Reports. 2016;6(4):618–32. PubMed PMID: 27050947; PubMed Central PMCID: PMC4834057.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Rishikaysh P, Dev K, Diaz D, Qureshi WM, Filip S, Mokry J. Signaling involved in hair follicle morphogenesis and development. Int J Mol Sci. 2014;15(1):1647–70. Epub 2014/01/24. PubMed PMID: 24451143; PubMed Central PMCID: PMC3907891.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bhattacharya S, Wheeler H, Leid M, Ganguli-Indra G, Indra AK. Transcription factor CTIP2 maintains hair follicle stem cell pool and contributes to altered expression of LHX2 and NFATC1. J Invest Dermatol. 2015. Epub 2015/07/16. PubMed PMID: 26176759.
  35. 35.
    Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ, Cotsarelis G. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med. 2005;11(12):1351–4. Epub 2005/11/17. PubMed PMID: 16288281.CrossRefPubMedGoogle Scholar
  36. 36.
    Liang X, Bhattacharya S, Bajaj G, Guha G, Wang Z, Jang HS, Leid M, Indra AK, Ganguli-Indra G. Delayed cutaneous wound healing and aberrant expression of hair follicle stem cell markers in mice selectively lacking Ctip2 in epidermis. PLoS One. 2012;7(2):e29999. Epub 2012/03/03. PubMed PMID: 22383956; PubMed Central PMCID: PMC3283611.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Botchkarev VA, Paus R. Molecular biology of hair morphogenesis: development and cycling. J Exp Zool B Mol Dev Evol. 2003;298(1):164–80. Epub 2003/09/02. PubMed PMID: 12949776.CrossRefPubMedGoogle Scholar
  38. 38.
    Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol. 2002;118(2):216–25. Epub 2002/02/14. PubMed PMID: 11841536.CrossRefPubMedGoogle Scholar
  39. 39.
    Suda T, Arai F. Wnt signaling in the niche. Cell. 2008;132(5):729–30. Epub 2008/03/11. PubMed PMID: 18329358.CrossRefPubMedGoogle Scholar
  40. 40.
    Jaks V, Kasper M, Toftgard R. The hair follicle-a stem cell zoo. Exp Cell Res. 2010;316(8):1422–8. Epub 2010/03/27. PubMed PMID: 20338163.CrossRefPubMedGoogle Scholar
  41. 41.
    Mardaryev AN, Meier N, Poterlowicz K, Sharov AA, Sharova TY, Ahmed MI, Rapisarda V, Lewis C, Fessing MY, Ruenger TM, Bhawan J, Werner S, Paus R, Botchkarev VA. Lhx2 differentially regulates Sox9, Tcf4 and Lgr5 in hair follicle stem cells to promote epidermal regeneration after injury. Development. 2011;138(22):4843–52. Epub 2011/10/27. PubMed PMID: 22028024; PubMed Central PMCID: PMC4067271.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Plikus MV, Gay DL, Treffeisen E, Wang A, Supapannachart RJ, Cotsarelis G. Epithelial stem cells and implications for wound repair. Semin Cell Dev Biol. 2012;23(9):946–53. Epub 2012/10/23. PubMed PMID: 23085626; PubMed Central PMCID: PMC3518754.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Horsley V, Aliprantis AO, Polak L, Glimcher LH, Fuchs E. NFATc1 balances quiescence and proliferation of skin stem cells. Cell. 2008;132(2):299–310. Epub 2008/02/05. PubMed PMID: 18243104; PubMed Central PMCID: PMC2546702.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Xiong Y, Li W, Shang C, Chen RM, Han P, Yang J, Stankunas K, Wu B, Pan M, Zhou B, Longaker MT, Chang CP. Brg1 governs a positive feedback circuit in the hair follicle for tissue regeneration and repair. Dev Cell. 2013;25(2):169–81. Epub 2013/04/23. PubMed PMID: 23602386.CrossRefPubMedGoogle Scholar
  45. 45.
    Alonso L, Fuchs E. The hair cycle. J Cell Sci. 2006;119(Pt 3):391–3. Epub 2006/01/31. PubMed PMID: 16443746.CrossRefPubMedGoogle Scholar
  46. 46.
    Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell. 2004;118(5):635–48. Epub 2004/09/02. PubMed PMID: 15339667.CrossRefPubMedGoogle Scholar
  47. 47.
    Levy V, Lindon C, Zheng Y, Harfe BD, Morgan BA. Epidermal stem cells arise from the hair follicle after wounding. FASEB J. 2007;21(7):1358–66. Epub 2007/01/27. PubMed PMID: 17255473.CrossRefPubMedGoogle Scholar
  48. 48.
    Nowak JA, Polak L, Pasolli HA, Fuchs E. Hair follicle stem cells are specified and function in early skin morphogenesis. Cell Stem Cell. 2008;3(1):33–43. Epub 2008/07/03. PubMed PMID: 18593557; PubMed Central PMCID: PMC2877596.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Snippert HJ, Haegebarth A, Kasper M, Jaks V, van Es JH, Barker N, van de Wetering M, van den Born M, Begthel H, Vries RG, Stange DE, Toftgard R, Clevers H. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science. 2010;327(5971):1385–9. Epub 2010/03/13. PubMed PMID: 20223988.CrossRefPubMedGoogle Scholar
  50. 50.
    Na J, Lee K, Na W, Shin JY, Lee MJ, Yune TY, Lee HK, Jung HS, Kim WS, Ju BG. Histone H3K27 Demethylase JMJD3 in cooperation with NF-kappaB regulates keratinocyte wound healing. J Invest Dermatol. 2016;136(4):847–58. PubMed PMID: 26802933.CrossRefPubMedGoogle Scholar
  51. 51.
    Odorisio T. Epigenetic control of skin Re-Epithelialization: the NF-kB/JMJD3 connection. J Invest Dermatol. 2016;136(4):738–40. PubMed PMID: 27012558.CrossRefPubMedGoogle Scholar
  52. 52.
    Menchon C, Edel MJ, Izpisua Belmonte JC. The cell cycle inhibitor p27Kip(1) controls self-renewal and pluripotency of human embryonic stem cells by regulating the cell cycle, Brachyury and Twist. Cell Cycle. 2011;10(9):1435–47. Epub 2011/04/12. PubMed PMID: 21478681; PubMed Central PMCID: PMC3685623.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Moloney FJ, Lyons JG, Bock VL, Huang XX, Bugeja MJ, Halliday GM. Hotspot mutation of Brahma in non-melanoma skin cancer. J Invest Dermatol. 2009;129(4):1012–5. Epub 2008/10/17. PubMed PMID: 18923443.CrossRefPubMedGoogle Scholar
  54. 54.
    Halliday GM, Zhou Y, Sou PW, Huang XX, Rana S, Bugeja MJ, Painter N, Scolyer RA, Muchardt C, Di Girolamo N, Lyons JG. The absence of Brm exacerbates photocarcinogenesis. Exp Dermatol. 2012;21(8):599–604. Epub 2012/07/11. PubMed PMID: 22775994.CrossRefPubMedGoogle Scholar
  55. 55.
    Hassan NM, Painter N, Howlett CR, Farrell AW, Di Girolamo N, Lyons JG, Halliday GM. Brm inhibits the proliferative response of keratinocytes and corneal epithelial cells to ultraviolet radiation-induced damage. PLoS One. 2014;9(9):e107931. Epub 2014/09/26. PubMed PMID: 25254962; PubMed Central PMCID: PMC4177874.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Halliday GM, Cadet J. It’s all about position: the basal layer of human epidermis is particularly susceptible to different types of sunlight-induced DNA damage. J Invest Dermatol. 2012;132(2):265–7. Epub 2012/01/14. PubMed PMID: 22241442.CrossRefPubMedGoogle Scholar
  57. 57.
    Lans H, Marteijn JA, Schumacher B, Hoeijmakers JH, Jansen G, Vermeulen W. Involvement of global genome repair, transcription coupled repair, and chromatin remodeling in UV DNA damage response changes during development. PLoS Genet. 2010;6(5):e1000941. Epub 2010/05/14. PubMed PMID: 20463888; PubMed Central PMCID: PMC2865526.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Indra AK, Warot X, Brocard J, Bornert JM, Xiao JH, Chambon P, Metzger D. Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res. 1999;27(22):4324–7. Epub 1999/10/28. PubMed PMID: 10536138; PubMed Central PMCID: PMC148712.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Metzger D, Indra AK, Li M, Chapellier B, Calleja C, Ghyselinck NB, Chambon P. Targeted conditional somatic mutagenesis in the mouse: temporally-controlled knock out of retinoid receptors in epidermal keratinocytes. Methods Enzymol. 2003;364:379–408. Epub 2003/11/25. PubMed PMID: 14631857.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, College of PharmacyOregon State UniversityCorvallisUSA
  2. 2.Molecular Cell Biology ProgramOregon State UniversityCorvallisUSA
  3. 3.Knight Cancer InstituteOregon Health & Science University (OHSU)PortlandUSA
  4. 4.Department of Biochemistry and BiophysicsOregon State UniversityCorvallisUSA
  5. 5.Linus Pauling InstituteOregon State UniversityCorvallisUSA
  6. 6.Departments of DermatologyOHSUPortlandUSA

Personalised recommendations