Science China Life Sciences

, Volume 58, Issue 9, pp 860–866 | Cite as

Exploring CTCF and cohesin related chromatin architecture at HOXA gene cluster in primary human fibroblasts

  • Xing Wang
  • Miao Xu
  • GuangNian Zhao
  • GuoYou Liu
  • DeLong Hao
  • Xiang LvEmail author
  • DePei LiuEmail author
Open Access
Research Paper


Spatial expression patterns of homeobox (HOX) genes delineate positional identity of primary fibroblasts from different topographic sites. The molecular mechanism underlying the establishing or maintaining of HOX gene expression pattern remains an attractive developmental issue to be addressed. Our previous work suggested a critical role of CTCF/cohesin-mediated higher- order chromatin structure in RA-induced HOXA activation in human teratocarcinoma NT2/D1 cells. This study investigated the recruitment of CTCF and cohesin, and the higher-order chromatin structure of the HOXA locus in fetal lung and adult foreskin fibroblasts, which display complementary HOXA gene expression patterns. Chromatin contacts between the CTCF-binding sites were observed with lower frequency in human foreskin fibroblasts. This observation is consistent with the lower level of cohesin recruitment and 5′ HOXA gene expression in the same cells. We also showed that CTCF-binding site A56 (CBSA56) related chromatin structures exhibit the most notable changes in between the two types of cell, and hence may stand for one of the key CTCF-binding sites for cell-type specific chromatin structure organization. Together, these results imply that CTCF/cohesin coordinates HOXA cluster higher-order chromatin structure and expression during development, and provide insight into the relationship between cell-type specific chromatin organization and the spatial collinearity.


human fibroblasts HOXA cluster higher-order chromatin structure CTCF cohesion 


  1. 1.
    Rinn JL, Bondre C, Gladstone HB, Brown PO, Chang HY. Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet, 2006, 2: e119Google Scholar
  2. 2.
    Chang HY, Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, Brown PO. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci USA, 2002, 99: 12877–12882PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Wang KC, Helms JA, Chang HY. Regeneration, repair and remembering identity: the three Rs of Hox gene expression. Trends Cell Biol, 2009, 19: 268–275PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Duboule D. The rise and fall of Hox gene clusters. Development, 2007, 134: 2549–2560PubMedCrossRefGoogle Scholar
  5. 5.
    Spitz F, Gonzalez F, Duboule D. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell, 2003, 113: 405–417PubMedCrossRefGoogle Scholar
  6. 6.
    Sharpe J, Nonchev S, Gould A, Whiting J, Krumlauf R. Selectivity, sharing and competitive interactions in the regulation of Hoxb genes. EMBO J, 1998, 17: 1788–1798PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Kmita M, Duboule D. Organizing axes in time and space; 25 years of colinear tinkering. Science, 2003, 301: 331–333PubMedCrossRefGoogle Scholar
  8. 8.
    Kondo T, Duboule D. Breaking colinearity in the mouse HoxD complex. Cell, 1999, 97: 407–417PubMedCrossRefGoogle Scholar
  9. 9.
    Roelen BA, de Graaff W, Forlani S, Deschamps J. Hox cluster polarity in early transcriptional availability: a high order regulatory level of clustered Hox genes in the mouse. Mech Dev, 2002, 119: 81–90PubMedCrossRefGoogle Scholar
  10. 10.
    Fraser J, Rousseau M, Shenker S, Ferraiuolo MA, Hayashizaki Y, Blanchette M, Dostie J. Chromatin conformation signatures of cellular differentiation. Genome Biol, 2009, 10: R37Google Scholar
  11. 11.
    Rousseau M, Crutchley JL, Miura H, Suderman M, Blanchette M, Dostie J. Hox in motion: tracking HoxA cluster conformation during differentiation. Nucleic Acids Res, 2014, 42: 1524–1540PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chambeyron S, Bickmore WA. Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. Genes Dev, 2004, 18: 1119–1130PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Noordermeer D, Leleu M, Splinter E, Rougemont J, De Laat W, Duboule D. The dynamic architecture of Hox gene clusters. Science, 2011, 334: 222–225PubMedCrossRefGoogle Scholar
  14. 14.
    Chambeyron S, Da Silva NR, Lawson KA, Bickmore WA. Nuclear re-organisation of the Hoxb complex during mouse embryonic development. Development, 2005, 132: 2215–2223PubMedCrossRefGoogle Scholar
  15. 15.
    Phillips JE, Corces VG. CTCF: master weaver of the genome. Cell, 2009, 137: 1194–1211PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Parelho V, Hadjur S, Spivakov M, Leleu M, Sauer S, Gregson HC, Jarmuz A, Canzonetta C, Webster Z, Nesterova T, Cobb BS, Yokomori K, Dillon N, Aragon L, Fisher AG, Merkenschlager M. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell, 2008, 132: 422–433PubMedCrossRefGoogle Scholar
  17. 17.
    Gause M, Schaaf CA, Dorsett D. Cohesin and CTCF: cooperating to control chromosome conformation? Bioessays, 2008, 30: 715–718PubMedCrossRefGoogle Scholar
  18. 18.
    Xu M, Zhao GN, Lv X, Liu G, Wang LY, Hao DL, Wang J, Liu DP, Liang CC. CTCF controls HOXA cluster silencing and mediates PRC2-repressive higher-order chromatin structure in NT2/D1 cells. Mol Cell Biol, 2014, 34: 3867–3879PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Li M, Ti D, Han W, Fu X. Microenvironment-induced myofibroblastlike conversion of engrafted keratinocytes. Sci China Life Sci, 2014, 57: 209–220PubMedCrossRefGoogle Scholar
  20. 20.
    Liu X, Huang Q, Li F, Li CY. Enhancing the efficiency of direct reprogramming of human primary fibroblasts into dopaminergic neuron-like cells through p53 suppression. Sci China Life Sci, 2014, 57: 867–875PubMedCrossRefGoogle Scholar
  21. 21.
    Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell, 2007, 129: 1311–1323PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, Baliga NS, Aebersold R, Ranish JA, Krumm A. CTCF physically links cohesin to chromatin. Proc Natl Acad Sci USA, 2008, 105: 8309–8314PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Kim YJ, Cecchini KR, Kim TH. Conserved, developmentally regulated mechanism couples chromosomal looping and heterochromatin barrier activity at the homeobox gene a locus. Proc Natl Acad Sci USA, 2011, 108: 7391–7396PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Yusufzai TM, Felsenfeld G. The 5′-HS4 chicken beta-globin insulator is a CTCF-dependent nuclear matrix-associated element. Proc Natl Acad Sci USA, 2004, 101: 8620–8624PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G. CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Mol Cell, 2004, 13: 291–298PubMedCrossRefGoogle Scholar
  26. 26.
    Hou C, Dale R, Dean A. Cell type specificity of chromatin organization mediated by CTCF and cohesin. Proc Natl Acad Sci USA, 2010, 107: 3651–3656PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© The Author(s) 2015

This article is published under license to BioMed Central Ltd. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical SciencesChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina

Personalised recommendations